INHIBITORS OF KEAP1-Nrf2 PROTEIN-PROTEIN INTERACTION

ABSTRACT

Sultam compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with the KEAP1-Nrf2 interaction, such as inflammatory bowel disease, including Crohn&#39;s disease and ulcerative colitis.

FIELD OF THE INVENTION

The present invention relates to certain sultam compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with the KEAP1-Nrf2 interaction.

BACKGROUND OF THE INVENTION

KEAP1 has been shown to interact with Nrf2, a regulator of the antioxidant response, which is important for the amelioration of oxidative stress. Nrf2 activation is desirable because it leads to coordinated antioxidant and anti-inflammatory responses. However, KEAP1 represses Nrf2 activation. So, there is interest in inhibiting the interaction that KEAP1 has with Nrf2.

In more detail, nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that comprises seven functional domains, Neh1 (Nrf2-ECH homology) to Neh7. Neh1 is a CNC-bZIP domain that allows Nrf2 to interact with small musculoaponeurotic fibrosarcoma (Maf) protein, other transcription partners, and DNA, while Neh3, Neh4, and Neh5 bind to other co-activators to enhance Nrf2 targeted gene expression. Neh2 contains two important motifs known as DLG and ETGE, which are essential for the interaction between Nrf2 and its negative regulator KEAP1 (Kelch-like ECH associated protein 1).

KEAP1 is a substrate adaptor for cullin-based E3 ubiquitin ligase, which binds to Nrf2 under basal conditions and inhibits the transcriptional activity of Nrf2 via ubiquitination and proteasomal degradation of Nrf2. The KELCH domains of the KEAP1 homodimer bind with the ETGE and DLG motifs of the Nrf2-Neh2 domain in the cytosol. Under oxidative stress, thiol modification of KEAP1 cysteine residues leads to conformational change in KEAP1 and dissociation of Nrf2 from KEAP1, which prevents Nrf2 ubiquitination and proteasomal degradation. Nrf2 then translocates into the nucleus and induces anti-oxidative responses by binding to ARE (antioxidant response element) in the promoter of antioxidant genes. More recently, Nrf2 has been shown to bind to promoter regions of pro-inflammatory cytokine genes (with or without ARE) and inhibit RNA Pol II recruitment, leading to inhibition of cytokine gene expression. In addition, Nrf2 negatively regulates the NF-kB signaling, a pathway that is involved in inflammation and apoptosis. Oxidative stress and inflammation are common features in many diseases. Nrf2 signaling pathway plays a critical role in antioxidant and anti-inflammatory responses by regulating >600 genes, many of which are associated with immune diseases. Preclinical and clinical data has demonstrated therapeutic potential of targeting the pathway in neuronal, kidney, cardiovascular, respiratory, eye, skin, and inflammatory bowel diseases. Nrf2 activators could also be useful for treatment of other neuronal diseases including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) (Mimoto, T. et al., Brain Research. 2012, 1446, 109-118) and Friedreich's Ataxia.

In the clinic, dimethyl fumarate, a covalent small molecule that can activate Nrf2 (among other targets) via robust modification of cysteine residues on KEAP1, and is approved in the U.S. to treat multiple sclerosis (MS). Another small molecule targeting the Nrf2 pathway by covalently modifying KEAP1, bardoxolone methyl, has shown clinical efficacy in chronic kidney disease (CKD) (Aleksunes, L. M., et al., J. Pharmacol. Exp. Ther. 2010, 335, 2-12), although the phase III trials were terminated due to adverse events. (Chin, M. P., et al., Am. J. Nephrol. 2014, 39, 499-508). There is an increasing body of evidence supporting a role for the KEAP1-Nrf2 ARE pathway in the regulation of physiological processes that serve to inhibit the development and progression of multiple diseases affecting the kidney (Shelton, L. M., et al., Kidney International 2013, 84, 1090-1095).

Despite the termination of bardoxolone methyl for CKD phase III trials, this drug has ongoing clinical trials in patients with pulmonary arterial hypertension ≤https://clinicaltrials.gov/ct2/show/NCT02036970>, accessed Nov. 20, 2017. Nrf2 activation may be involved in myocardial repair and cardiac remodeling and useful for treatment of cardiovascular diseases including but not limited to atherosclerosis (Niture, S. K., et al., Free Radic. Biol. Med. 2014, 66, 36-44), hypertension, and heart failure (Howden, R. Oxidative Medicine and Cellular Longevity 2013, 1-10), acute coronary syndrome, myocardial infarction, cardiac arrhythmias, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction and diabetic cardiomyopathy. (Jiang, S. et al., Expert Opinion on Therapeutic Targets 2016, 20, 1413-1424).

The modulation of the KEAP1-Nrf2 interaction is an attractive approach for intervention and prevention strategies in chronic obstructive pulmonary disease (COPD) (Davies, T. G. et al., J. Med. Chem. 2016, 59, 3991-4006). Evidence suggests that low Nrf2 activity in the lung contributes to the pathophysiology of COPD (Yamada, K., et al., BMC Pulmonary Medicine, 2016, 16, 27), probably due to an altered equilibrium between positive and negative Nrf2 regulators. Compared to wild-type littermates, Nrf2 knockout mice show more pronounced inflammation and neutrophilic elastase activity in the bronchoalveolar lavage and exhibit a higher susceptibility to cigarette smoke—or elastase-induced pulmonary emphysema. Conversely, KEAP1 deletion in the lungs activates Nrf2 signaling and attenuates acute cigarette smoke-induced oxidative stress and inflammation in mice (Boutten, A., et al., Trends Mol. Med. 2011, 17, 363-371). Molecules targeting the KEAP1-Nrf2 protein-protein interaction may treat COPD and other respiratory diseases such as asthma, pulmonary fibrosis (Cho, H-Y., et al., Toxicol. Appl. Pharmacol. 2010, 244, 43-56, Adenuga, D. et al., Biochem. Biophys. Res. Commun. 2010, 403, (3-4), 452-456), and cigarette smoke-induced emphysema (Iizuka, T. et al., Genes to Cells, 2005, 10 (12) 1113-1125.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is an inappropriate immune response to environmental changes and the intestinal microbiota in a genetically susceptible background. Accumulating data from both experimental models and clinical studies indicate that oxidative stress and Nrf2 signaling dysfunction contributes to the development of IBD.

Increased reactive oxygen species (ROS) and oxidative injury have been demonstrated in intestinal mucosa of patients with either UC or CD (Cracowski, J-L., et al., Am. J. Gastroenterol. 2002, 97, 99-103; Hatsugai, M., et al., J. Gastroenterol. 2010, 45, 488-500). On the other hand, the levels of intestinal mucosal antioxidants are reduced in IBD patients as compared with control subjects (Rezaie, A., et al., Dig. Dis. Sci. 2007, 52, 2015-2021; Kruidenier, L., et al., Aliment Pharmacol. Ther. 2002, 16, 1997-2015; Catarzi, S., et al., Inflamm. Bowel Dis. 2011, 17, 1674-84). The antioxidant levels and the oxidative stress biomarkers are usually correlated with the disease severity and the extent of intestinal inflammation in the IBD patients. Many of the reduced antioxidants in IBD, including glutathione, glutathione S-transferase (GST), superoxide dismutase, catalase, paraoxonase-1 and metallothionein, are regulated by Nrf2.

Genome-wide association studies have linked IBD-associated single nucleotide polymorphisms (SNPs) to the genes involved in oxidative stress response (e.g. GPX1, GPX4, PARK7, BACH2, PRDX5, ADO, SLC22A4, LRRK2, NOD2, CARD9, HSPA6, DLD, UTS2, and PEX13) (Khor, B., et al. Nature 2011, 474(7351), 307-317), many of which are Nrf2 targeted genes or regulators of Nrf2 signaling.

In line with these findings, a mutation in Nrf2 gene promoter decreases Nrf2 expression and predisposes to UC in a Japanese population (Arisawa, T. et al. Hepato-Gastroenterology 2008, 55, 394-397). In addition, one of the strongest epidemiologic observations in the IBD field is that cigarette smoking is protective against the development of UC (Cope, G. F., et al., Human Toxicol. 1987, 6, 189-193) and the effect is linked to Nrf2 activation by a prominent component of cigarette smoke, carbon monoxide (CO) (Onyiah, J. C. et al., Gut Microbes 2014, 5(2), 220-224).

Preclinical data indicates that Nrf2 plays an important role in protecting intestinal integrity and preserving tolerance to the enteric microbiota. Nrf2 knockout mice were found to be more susceptible to DSS-induced colitis, with a substantial loss of crypts compared with those of wild-type. The increased severity of colitis in Nrf2 knockout mice was found to be associated with decreased expression of antioxidant/phase II detoxifying enzymes including heme-oxygenase-1 (HO-1), NAD(P)H-quinone reductase-1 (NQO1), UDP-glucurosyltransferase 1A1 (UGT1A1), and glutathione S-transferase Mu-1 (GSTM1), and increased expression of proinflammatory genes, including IL-10, IL-6, IL-8, iNOS, and COX-2 (Khor, T. O., et al., Cancer Res. 2006, 66(24), 11580-11584). In addition, it was demonstrated that enteric microbiota activates Nrf2, leading to induction of Nrf2 targeted genes such as HO-1. Nrf2 activation/HO-1 induction prevents enteric microbiota induced colitis in IL-10 knockout mice, with augmented bacterial clearance (Onyiah, J. C., et al., Gastroenterology 2013, 144, 789-798). More recently, a non-covalent KEAP1-Nrf2 small molecule protein-protein-interaction (PPI) inhibitor was shown to protect human colonic cells against stress-induced cell damage in vitro and ameliorate DSS-induced colitis in mice (Lu, M. C., et al., Nature, Sci Rep. 2016, 6, 26585). The same molecule was also shown to dampen LPS-induced serum cytokines in mice (TNFα, IFNγ, IL-6, IL-12, IL-17) (Jiang, Z-Y., et al., J. Med. Chem. 2015, 58(16), 6410-6421).

Oxidative stress leads to damages of the mucosal layer in the GI tract and bacterial invasion, which in turn stimulates the immune response and initiates IBD. Nrf2 can maintain mucosa homeostasis by protecting against oxidative injury and proinflammatory response in IBD. Thus, pharmacological activation of Nrf2 signaling may represent an effective strategy for the intervention of human IBD (Almenier, H. A. et al., Fronteirs in Bioscience E4, 2012, 1335-1344).

The KEAP1-Nrf2 interaction has also been implicated in skin diseases such as psoriasis (Kadam, D. P., et al., Ind. J. Clin. Biochem. 2010, 25(4), 388-392) and inflammatory eye diseases such as age-related macular degeneration (Schimel, A. M. et al., Am. J. Pathol. 2011, 178, 2032-2043), Fuchs Endothelial Corneal Dystrophy (FECD) (Bitar, M. S. et al., 2012, Invest. Ophthalmol. Visual Sci, 2012, 53 (9), 5806-5813), uveitis and other inflammatory eye conditions. Nrf2 activation may have potential in treating oxidative stress-related inflammatory diseases in general. In addition, KEAP1-Nrf2 interaction inhibitors—shortly also referred to herein as “KEAP1-Nrf2 inhibitors” are envisaged as treatment candidates for other diseases (Abed, D. A. et al., Acta Pharmaceutica Sinica B, 2015, 5 (4), 285-299). They are envisaged for use in the treatment of type-1 diabetes (Aleksunes, L. M. et al., J. Pharmacol. Exp. Ther. 2010, 333 (1), 140-151), type-2 diabetes (Bitar, M. S. et al., Am. J. Phsiol. Endocrinol. Metab. 2011, 301 (6), E1119-1129; Rochette, L. et al., Biochimica et Biophysica Acta 2014, 1840 (9), 2709-2729, Bhakkiyalakshmi, E. et al., Pharmacol. Research 2015, 91, 104-114), and insulin resistance (Houstis, N. et al., Nature, 2006, 440 (7086) 944-948), sepsis-induced acute kidney injury and acute kidney injury (see Shelton, 2013, cited above), preeclampsia (Kweider, N. et al., Annals of Anatomy, 2014, 196, 268-277), acute mountain sickness (Lisk, C. et al., Free Radical Biology and Medicine, 2013, 63, 264-273), dermatitis and topical effects of radiation (Schafer, M. et al., Genes and Development 2010, 24(10), 1045), immunosuppression due to radiation exposure (Kim, J.-H. et al., J. Clin. Investigation 2014, 124, 730-741), non-alcoholic steatohepatitis (Shimozono, R. et al., Mol. Pharmacol. 2013, 84, 62-70; Chowdry, S. et al., Free Radical Biology and Medicine, 2010, 48, 357-371), viral hepatitis, cirrhosis, and toxin-induced liver disease such as acetaminophen-induced hepatic disease (see Howden, 2013, cited above).

BRIEF SUMMARY OF THE INVENTION

Embodiments of the present invention relate to compounds, pharmaceutical compositions containing them, methods of making and purifying them, methods of using them as KEAP1-Nrf2 inhibitors and methods for using them the treatment of disease states, disorders, and conditions associated with the KEAP1-Nrf2 interaction. An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition associated with the KEAP1-Nrf2 interaction using compounds of the invention or active agents of the invention.

Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

Embodiments of this invention are compounds of Formula (I), and pharmaceutically acceptable salts thereof

wherein

-   -   X is CH or N;     -   Q is CH or N;     -   M is CH or N;         -   wherein         -   when X is N, each of Q and M is CH;         -   when Q is N, each of X and M is CH; and         -   when M is N, each of X and Q are CH;     -   R¹⁵ is CH₃ or Cl;     -   R¹³ is H, F or C₁-C₄alkyl;     -   R¹⁴ is H, F or C₁-C₄alkyl;

HetA is selected from the group consisting of

wherein

-   -   R¹ is selected from the group consisting of C₃-C₄cycloalkyl,         C₁-C₄alkyl and C₁-C₄alkyl monosubstituted with cyclopropyl or         cyclobutyl;     -   R² is selected from the group consisting of H, C₁-C₄alkyl and         C₁-C₄perhaloalkyl;     -   R³ is H or C₁-C₄alkyl;     -   R⁴ is selected from the group consisting of C₁-C₄alkyl,         C₁-C₄perhaloalkyl and C₃-C₄cycloalkyl;     -   R⁷ is H or C₁-C₄alkyl;     -   R⁸ is C₁-C₄alkyl;     -   R⁹ is C₁-C₄alkyl;     -   R¹⁰ is selected from the group consisting of H,         —OC₃-C₄cycloalkyl and —OC₁-C₄perhaloalkyl;

HetB is selected from the group consisting of

wherein

-   -   Z is selected from the group consisting of O, CH₂, NH and         N(CH₃);     -   T is CH or N;     -   Y is CH or N;     -   W is CH or N;     -   V is O or N(CH₃);

R¹⁶ is H or F;

-   -   R¹⁷ is H or F;     -   n is 0, 1 or 2;     -   R¹⁸ is selected from the group consisting of H, —CN, halo,         C(O)NH₂, C₁-C₄alkyl and C₁-C₄perhaloalkyl;     -   R¹⁹ is selected from the group consisting of H; CN; halo;         C(O)NH₂;         -   N(R³⁸)C₁-C₆alkyl; C₁-C₄alkyl; C₁-C₄perhaloalkyl;

OC₁-C₆alkyl;

-   -   -   OC₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of —OH, —OCH₃,             —O(CH₂)₃OH, —N(R³⁶)R³⁷, C₁-C₄alkyl,

-   -   -   —N(R³⁸)C₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of OH, —OCH₃, —N(R³⁶)R³⁷,             C₁-C₄alkyl,

and

-   -   -   C₁-C₄alkyl monosubstituted with a substituent selected from             the group consisting of —C(O)NHCH₂CH₂OH,             —C(O)NHCH₂CH₂OCH₂CH₂NH₂, C(O)NH₂ and OH;

    -   R²⁰ is H or C₁-C₄alkyl;

    -   R²¹ is selected from the group consisting of H, —CN, halo,         C₁-C₄alkyl and C₁-C₄perhaloalkyl;

    -   R²² and R²³ are taken together with the carbon to which they are         attached to form         -   (a) the moiety

wherein R is selected from the group consisting of CH₂,

-   -   -   NR³⁸ and O, m is 0 or 1, and p is 0 or 1; or         -   (b) the moiety

-   -   R^(22′) is selected from the group consisting of H, C₁-C₄alkyl         and C₃-C₄cycloalkyl, and     -   R^(23′) is selected from the group consisting of H, C₁-C₄alkyl         and C₃-C₄cycloalkyl;     -   R²⁴ is selected from the group consisting of H; CN; halo;         C(O)NH₂;         -   C(O)(NH)C₃-C₄cycloalkyl N(R³⁸)C₁-C₆alkyl; C₁-C₄alkyl;             C₁-C₄perhaloalkyl;

OC₁-C₆alkyl;

-   -   -   OC₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of —OH, —OCH₃,             —O(CH₂)₃OH, —N(R³⁶)R³⁷, C₁-C₄alkyl;

-   -   -   —N(R³⁸)C₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of OH, —OCH₃, —N(R³⁶)R³⁷,             C₁-C₄alkyl,

and

-   -   -   C₁-C₄alkyl monosubstituted with a substituent selected from             the group consisting of —C(O)NHCH₂CH₂OH,             —C(O)NHCH₂CH₂OCH₂CH₂NH₂, C(O)NH₂ and OH;

    -   R²⁵ is selected from the group consisting of H; CN; halo;         C(O)NH₂;         -   N(R³⁸)C₁-C₆alkyl; C₁-C₄alkyl; C₁-C₄perhaloalkyl;

OC₁-C₆alkyl;

-   -   -   OC₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of —OH, —OCH₃,             —O(CH₂)₃OH, —N(R³⁶)R³⁷, C₁-C₄alkyl,

-   -   -   —N(R³⁸)C₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of OH, —OCH₃, —N(R³⁶)R³⁷,             C₁-C₄alkyl,

and

-   -   -   C₁-C₄alkyl monosubstituted with a substituent selected from             the group consisting of —C(O)NHCH₂CH₂OH,             —C(O)NHCH₂CH₂OCH₂CH₂NH₂, C(O)NH₂ and OH;

    -   R²⁶ is selected from the group consisting of H, —CN, halo,         C₁-C₄alkyl and C₁-C₄perhaloalkyl;

    -   R²⁷ is H or C₁-C₄alkyl;

    -   R³⁶ and R³⁷ are independently selected from the group consisting         of H and C₁-C₄alkyl;

    -   R³⁸ is H or C₁-C₄alkyl;

    -   provided that when HetA is

then HetB is not

Illustrative embodiments of Formula (I) are compounds selected from the group consisting of

-   3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid -   (*S)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2%3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (R)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methy-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,3′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6     (7H)-yl)methyl)-4-methylphenyl)propanoic acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)     3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepin]-4,1′-cyclopropan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl]-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-Chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxyethyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxypropyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-Hydroxy-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((3-Methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Hydroxypropyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Hydroxyethyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-((7′-((2-morpholinoethyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethyl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(Butylamino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((R)-3-Hydroxy-3-methylbutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((1s,3S)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(3-((2-Hydroxy     ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (3*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (3*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; -   (3*R)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; -   (3*S)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; -   (R/S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4methylphenyl)-3(1ethyl-4methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-[3-[(5,5-Dioxo-7a,8,9,10-tetrahydro-7H-pyrrolo[2,1-d][1,2,5]benzothiadiazepin-6-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic     acid; -   (*R)-3-[3-[(5,5-Dioxo-7a,8,9,10-tetrahydro-7H-pyrrolo[2,1-d][1,2,5]benzothiadiazepin-6-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic     acid; -   (R/S)-3-[3-[(4,4-Dimethyl-1,1-dioxo-3H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic     acid; -   (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (R/S)-3-(4-Methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-(((S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(t*rifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (3*S)-3-(3-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*s)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3     f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-4-Ethyl-8-methyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-Chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-2-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-2-Carbamoyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-2-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-2-Carbamoyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro     1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; and -   (*R)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-b][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(3-((2-(2-Aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(3-((2-(2-aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin     1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidine     1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidine     1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidine     1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′-(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-((7′-((2-(4,4-Difluoropiperidin-1-yl)ethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((1R,3R)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((R-1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((S-1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(pyrrolidine     1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxido-7′-((2-(piperazin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-(8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-4-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin     1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-piperidin-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin     1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-((7′-(2-(4-Methoxypiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)     1-piperidin 1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido     [2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-(((*R)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*R)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (3     S*)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (S)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R*)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (S*)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R*)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-difluoro-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6     (7H)-yl)methyl)-4-methylphenyl)propanoic acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6     (7H)-yl)methyl)-4-methylphenyl)propanoic acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6     (7H)-yl)methyl)-4-methylphenyl)propanoic acid; -   3-(3-((10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3     f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-10,10-difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro     [1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic     acid; -   3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic     acid; -   3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (3*S)-3-(6-(((S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (3*R)-3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (3*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (3*S)-2-Methyl-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (3*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic     acid; -   3-(6-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((7′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (2*S,3*R)-2-Methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (2*R,3*R)-2-Methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide; -   3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (2S,3*R)-3-(3-(Trifluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)     [1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7-(2-morpholinoethoxy)     1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)     1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-di     oxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-di     oxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-di     oxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-(3-fluoroazetidin     1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(3-amino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*S)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-(Azetidin 1-yl)ethoxy)     8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(3-Cyclobutyl     amino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxyethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(3-(3-Hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(3-(3-Hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(5-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(5-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(5-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(5-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid     (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)pyridin-2-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “including”, “containing” and “comprising” are used in their open, non-limiting sense.

Unless qualified specifically in particular instances of use, the term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. “C₁-C₄alkyl” refers to straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain.

The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:

The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

The term “perhaloalkyl” or “haloalkyl” refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain optionally substituting hydrogens with halogens. The term “C₁-C₄ haloalkyl” as used here refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally substituting hydrogens with halogens. Examples of “perhaloalkyl”, “haloalkyl” groups include trifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl (CH₂F), pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl (CH₂CH₂F), trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl (CF(CF₃)₂), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

Those of ordinary skill in the art will recognize that the species of cycloalkyl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.

Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of such formula. The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Thus, any formula given herein is intended to represent a racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, polymorphs and of such compounds, and mixtures thereof, even if such forms are not listed explicitly.

Reference to a compound herein stands for a reference to any one of: (a) the actually recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named. For example, reference herein to a compound such as R—COOH, encompasses reference to any one of, for example, R—COOH(s), R—COOH(sol), and R—COO-(sol). In this example, R—COOH(s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation; R—COOH(sol) refers to the undissociated form of the compound in a solvent; and R—COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R—COOH, from a salt thereof, or from any other entity that yields R—COO— upon dissociation in the medium being considered. In another example, an expression such as “exposing an entity to compound of formula R—COOH” refers to the exposure of such entity to the form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such exposure takes place. In still another example, an expression such as “reacting an entity with a compound of formula R—COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such reacting takes place. In this regard, if such entity is for example in an aqueous environment, it is understood that the compound R—COOH is in such same medium, and therefore the entity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq), where the subscript “(aq)” stands for “aqueous” according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been chosen in these nomenclature examples; this choice is not intended, however, as a limitation but it is merely an illustration. It is understood that analogous examples can be provided in terms of other functional groups, including but not limited to hydroxyl, basic nitrogen members, such as those in amines, and any other group that interacts or transforms according to known manners in the medium that contains the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation, and deprotonation. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number in an enriched form. Examples of isotopes that can be incorporated into compounds of the invention in a form that exceeds natural abundances include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The term Cn-m alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n≤N≤m, with m>n.

When the same plurality of substituents is assigned to various groups, the specific individual substituent assignment to each of such groups is meant to be independently made with respect to the specific individual substituent assignments to the remaining groups. By way of illustration, but not as a limitation, if each of groups Q and R can be H or F, the choice of H or F for Q is made independently of the choice of H or F for R, so the choice of assignment for Q does not determine or condition the choice of assignment for R, or vice-versa, unless it is expressly indicated otherwise. Illustrative claim recitation in this regard would read as “each of Q and R is independently H or F”, or “each of Q and R is independently selected from the group consisting of H and F”.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

In another example, a zwitterionic compound would be encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form. Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names. In this regard, the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As generally well known, a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term “inner salts”. Other sources refer to these compounds as “dipolar ions”, although the latter term is regarded by still other sources as a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well-established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because the interactions and transformations in a given medium that lead to the various forms of a given compound are known by any one of ordinary skill in the art.

When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same choice of the species for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹ _(example) is one of S₁ and S₂, and substituent S² _(example) is one of S₃ and S₄, then these assignments refer to embodiments of this invention given according to the choices S¹ _(example) is S₁ and S² _(example) is S₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ and S² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; and equivalents of each one of such choices. The shorter terminology “S¹ _(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein.

Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent S_(example) is one of S₁, S₂, and S₃, this listing refers to embodiments of this invention for which S_(example) is S₁; S_(example) is S₂; S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is one of S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁, S₂ and S₃; and S_(example) is any equivalent of each one of these choices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃” is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein.

The nomenclature “C_(i)-C_(j)” with j>i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C₁-C₃ refers independently to embodiments that have one carbon member (C₁, embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

A “pharmaceutically acceptable salt” is intended to mean a salt of an acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.

A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

Compounds of Formula (I) may contain at least one nitrogen of basic character, so desired pharmaceutically acceptable salts may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents.

Since compounds of Formula (I) contain a carboxylic acid moiety, a desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, piperazine, N-methyl-glucamine and tromethamine and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The compounds of the invention, including their pharmaceutically acceptable salts, whether alone or in combination, (collectively, “active agent” or “active agents”) of the present invention are useful as KEAP1-Nrf2 inhibitors in the methods of the invention. Such methods for modulating KEAP1-Nrf2 interaction comprise the use of an effective amount of at least one chemical compound of the invention.

In some embodiments, the KEAP1-Nrf2 inhibitor is used in a subject diagnosed with or suffering from a disease, disorder, or medical condition associated with KEAP1-Nrf2 interaction, such as those described herein. Symptoms or disease states are intended to be included within the scope of “disease, disorders or medical conditions.”

Accordingly, the invention relates to methods of using the active agents described herein to treat subjects diagnosed with or suffering from a disease, disorder, or medical condition associated with the KEAP1-Nrf2 interaction. The term “treat” or “treating” as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of KEAP1-Nrf2 interaction. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition associated with the KEAP1-Nrf2 interaction. The term “subject” refers to a mammalian patient in need of such treatment, such as a human. The term “inhibitors” or “inhibitor” refers to compounds that decrease, prevent, inactivate, desensitize or down-regulate the KEAP1-Nrf2 interaction.

In treatment methods according to the invention, an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. An “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. For a 70-kg human, an illustrative range for a suitable dosage amount is from about 1 to 1000 mg/day in single or multiple dosage units (e.g., BID, TID, QID or as required by modality).

Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventive or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention are envisaged for use alone, in combination with one or more of other compounds of this invention, or in combination with additional active ingredients in the treatment of the conditions discussed below. The additional active ingredients may be co-administered separately with at least one compound of the invention, with active agents of the invention or included with such an agent in a pharmaceutical composition according to the invention. In an illustrative embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases associated with the KEAP1-Nrf2 interaction, such as another KEAP1-Nrf2 inhibitor or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.

When referring to inhibiting the target, an “effective amount” means an amount sufficient to affect KEAP1-Nrf2 interaction.

The active agents of the invention are envisaged for use, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises an effective amount of at least one active agent in accordance with the invention.

Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using pharmaceutically acceptable excipients and compounding techniques known or that become available to those of ordinary skill in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. The compositions may be formulated for any one of a plurality of administration routes, such as intravenous infusion, topical administration, or oral administration. Preferably, the compositions may be formulated for oral administration.

For oral administration, the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be formulated to yield a dosage of, e.g., for a 70-kg human, an illustrative range for a suitable dosage amount is from about 1 to 1000 mg/day in single or multiple dosage units.

Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.

Illustrative examples of liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are examples of disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin or (hydroxypropyl)methyl cellulose capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository, enema or foam. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20% of drug to vehicle, preferably 0.1% to 10%. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.

Active agents may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

In a further embodiment, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition associated with KEAP1-Nrf2 interaction, comprising administering to the subject in need of such treatment an effective amount of the active agent.

In certain embodiments of the inventive method, the disease, disorder, or medical condition is an inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.

Other embodiments of this invention provide for a method for modulating KEAP1-Nrf2 interaction, including when KEAP1-Nrf2 interaction is in a subject, comprising exposing KEAP1-Nrf2 to an effective amount of at least one compound selected from compounds of the invention.

Embodiments of this invention are compounds of Formula (I), and pharmaceutically acceptable salts thereof

wherein

-   -   X is CH or N;     -   Q is CH or N;     -   M is CH or N;         -   wherein         -   when X is N, each of Q and M is CH;         -   when Q is N, each of X and M is CH; and         -   when M is N, each of X and Q are CH;     -   R¹⁵ is CH₃ or Cl;     -   R¹³ is H, F or C₁-C₄alkyl;     -   R¹⁴ is H, F or C₁-C₄alkyl;     -   HetA is selected from the group consisting of

wherein

-   -   R¹ is selected from the group consisting of C₃-C₄cycloalkyl,         C₁-C₄alkyl and C₁-C₄alkyl monosubstituted with cyclopropyl or         cyclobutyl;     -   R² is selected from the group consisting of H, C₁-C₄alkyl and         C₁-C₄perhaloalkyl;     -   R³ is H or C₁-C₄alkyl;     -   R⁴ is selected from the group consisting of C₁-C₄alkyl,         C₁-C₄perhaloalkyl and C₃-C₄cycloalkyl;     -   R⁷ is H or C₁-C₄alkyl;     -   R⁸ is C₁-C₄alkyl;     -   R⁹ is C₁-C₄alkyl;     -   R¹⁰ is selected from the group consisting of H,         —OC₃-C₄cycloalkyl and —OC₁-C₄perhaloalkyl;     -   HetB is selected from the group consisting of

wherein

-   -   Z is selected from the group consisting of 0, CH₂, NH and         N(CH₃);     -   T is CH or N;     -   Y is CH or N;     -   W is CH or N;     -   V is O or N(CH₃);     -   R¹⁶ is H or F;     -   R¹⁷ is H or F;     -   n is 0, 1 or 2;     -   R¹⁸ is selected from the group consisting of H, —CN, halo,         C(O)NH₂, C₁-C₄alkyl and C₁-C₄perhaloalkyl;     -   R¹⁹ is selected from the group consisting of H; CN; halo;         C(O)NH₂;         -   N(R³⁸)C₁-C₆alkyl; C₁-C₄alkyl; C₁-C₄perhaloalkyl;

OC₁-C₆alkyl;

-   -   -   OC₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of —OH, —OCH₃,             —O(CH₂)₃OH, —N(R³⁶)R³⁷, C₁-C₄alkyl,

-   -   -   —N(R³⁸)C₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of OH, —OCH₃, —N(R³⁶)R³⁷,             C₁-C₄alkyl,

and

-   -   -   C₁-C₄alkyl monosubstituted with a substituent selected from             the group consisting of —C(O)NHCH₂CH₂OH,             —C(O)NHCH₂CH₂OCH₂CH₂NH₂, C(O)NH₂ and OH;

    -   R²⁰ is H or C₁-C₄alkyl;

    -   R²¹ is selected from the group consisting of H, —CN, halo,         C₁-C₄alkyl and C₁-C₄perhaloalkyl;

    -   R²² and R²³ are taken together with the carbon to which they are         attached to form         -   (a) the moiety

wherein R is selected from the group consisting of CH₂, NR³⁸ and O, m is 0 or 1, and p is 0 or 1; or

-   -   -   (b) the moiety

-   -   R^(22′) is selected from the group consisting of H, C₁-C₄alkyl         and C₃-C₄cycloalkyl, and     -   R^(23′) is selected from the group consisting of H, C₁-C₄alkyl         and C₃-C₄cycloalkyl;     -   R²⁴ is selected from the group consisting of H; CN; halo;         C(O)NH₂;         -   C(O)(NH)C₃-C₄cycloalkyl; N(R³⁸)C₁-C₆alkyl; C₁-C₄alkyl;             C₁-C₄perhaloalkyl;

OC₁-C₆alkyl;

-   -   -   OC₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of —OH, —OCH₃,             —O(CH₂)₃OH, —N(R³⁶)R³⁷, C₁-C₄alkyl;

-   -   -   —N(R³⁸)C₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of OH, —OCH₃, —N(R³⁶)R³⁷,             C₁-C₄alkyl,

and

-   -   -   C₁-C₄alkyl monosubstituted with a substituent selected from             the group consisting of —C(O)NHCH₂CH₂OH,             —C(O)NHCH₂CH₂OCH₂CH₂NH₂, C(O)NH₂ and OH;

    -   R²⁵ is selected from the group consisting of H; CN; halo;         C(O)NH₂;         -   N(R³⁸)C₁-C₆alkyl; C₁-C₄alkyl; C₁-C₄perhaloalkyl;

OC₁-C₆alkyl;

-   -   -   OC₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of —OH, —OCH₃,             —O(CH₂)₃OH, —N(R³⁶)R³⁷, C₁-C₄alkyl,

-   -   -   —N(R³⁸)C₁-C₆alkyl substituted with one or two substituents             selected from the group consisting of OH, —OCH₃, —N(R³⁶)R³⁷,             C₁-C₄alkyl,

and

-   -   -   C₁-C₄alkyl monosubstituted with a substituent selected from             the group consisting of —C(O)NHCH₂CH₂OH,             —C(O)NHCH₂CH₂OCH₂CH₂NH₂, C(O)NH₂ and OH;

    -   R²⁶ is selected from the group consisting of H, —CN, halo,         C₁-C₄alkyl and C₁-C₄perhaloalkyl;

    -   R²⁷ is H or C₁-C₄alkyl;

    -   R³⁶ and R³⁷ are independently selected from the group consisting         of H and C₁-C₄alkyl;

    -   R³⁸ is H or C₁-C₄alkyl;

    -   provided that when HetA is

then HetB is not

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is C₁-C₄alkyl, R¹⁰ is H and R² is C₁-C₄alkyl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is C₁-C₄alkyl, R¹⁰ is H and R² is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is C₁-C₂alkyl, R¹⁰ is H and R² is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₂CH₃, R¹⁰ is H and R² is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₃, R¹⁰ is H and R² is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

and R⁴ is C₁-C₄alkyl or C₁-C₄perhaloalkyl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

and R⁴ is C₁-C₄perhaloalkyl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

and R⁴ is C₁-C₂perhaloalkyl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

and R⁴ is CF₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is C₁-C₄perhaloalkyl, R³ is C₁-C₄alkyl and R⁷ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is C₁-C₂perhaloalkyl, R³ is C₁-C₄alkyl and R⁷ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is C₁-C₂perhaloalkyl, R³ is C₁-C₂alkyl and R⁷ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is C₁-C₂perhaloalkyl, R³ is CH₃ and R⁷ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃ and R⁷ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein X is N.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein X is CH.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein Q is N.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein Q is CH.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein M is N.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein M is CH.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹⁵ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹⁵ is Cl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹³ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹³ is CH₃ and R¹⁴ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹³ is CH₃ and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹³ is H and R¹⁴ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃, R⁷ is H and X is N.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃, R⁷ is H, X is N and R¹⁵ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃, R⁷ is H, X is N, R¹⁵ is CH₃, R¹³ is H and R¹⁴ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃, R⁷ is H, X is N, R¹⁵ is CH₃, R¹³ is CH₃ and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃, R⁷ is H and X is CH.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R⁴ is CF₃, R³ is CH₃, R⁷ is H, X is CH, and R¹⁵ is Cl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₂CH₃, R¹⁰ is H, R² is CH₃ and X is N.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₂CH₃, R¹⁰ is H, R² is CH₃, X is N, R¹⁵ is CH₃, R¹³ is H and R¹⁴ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₂CH₃, R¹⁰ is H, R² is CH₃, X is N and R¹⁵ is Cl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₂CH₃, R¹⁰ is H, R² is CH₃, X is CH, R¹⁵ is CH₃, R¹⁻³ is H and R¹⁴ is H.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

R¹ is CH₂CH₃, R¹⁰ is H, R² is CH₃, X is CH and R¹⁵ is Cl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is selected from the group consisting of

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is selected from the group consisting of

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is CH₂ or O, m is 0 or 1, and p is 0 or 1.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 0 or 1, and p is 0 or 1.

An additional illustrative embodiment of the invention is a compound of Formula (I), HetB is

R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, and p is 1.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is C₁-C₄alkyl, and R¹⁴ is C₁-C₄alkyl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetB is

R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

HetB is

R⁴ is CF₃, R³ is CH₃, R⁷ is H, X is CH, R¹⁵ is CH₃, R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, and R¹⁴ is CH₃

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

HetB is

R⁴ is CHF₂, R³ is CH₃, R⁷ is H, X is CH, Q is CH, M is CH, W is N, R²⁴ is H, R²¹ is H, R¹⁵ is CH₃, R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein

HetA is

HetB is

R⁴ is CF₃, R³ is CH₃, R⁷ is H, X is CH, R¹⁵ is CH₃, R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, R¹⁴ is CH₃ and R²⁴ is OC₂-C₄alkyl or OC₂-C₄alkyl is substituted with

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

HetB is

R⁴ is cyclopropyl, R³ is CH₃, R⁷ is H, X is CH, Q is CH, M is CH, R¹⁵ is CH₃, R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein

HetA is

HetB is

R¹ is CH₂CH₃, R² is CH₃, R¹⁰ is H, X is CH, Q is CH, M is N, R¹⁵ is CH₃, R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein HetA is

HetB is

R¹ is cyclopropyl, R² is CH₃, R¹⁰ is H, X is CH, Q is CH, M is N, R¹⁵ is CH₃, R²² and R²³ are taken together with the carbon to which they are attached to form the moiety

wherein R is O, m is 1, p is 1, R¹³ is CH₃, and R¹⁴ is CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹ is C₁-C₄alkyl that is substituted with one of cyclopropyl and cyclobutyl.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹⁸ is OC₁-C₄alkyl substituted with one of —OH, —N(R³⁶)R³⁷ and

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹⁸ is NHC₁-C₄alkyl substituted with one of OH and CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R¹⁸ is C₁-C₄alkyl is substituted with one of C(O)NHCH₂CH₂OH and OH.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R²⁴ is OC₁-C₄alkyl substituted with one of —OH, —N(R³⁶)R³⁷ and

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R²⁴ is NHC₁-C₄alkyl substituted with one of OH and CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R²⁴ is C₁-C₄alkyl is substituted with one of C(O)NHCH₂CH₂OH and OH.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R²⁵ is OC₁-C₄alkyl substituted with one of —OH, —N(R³⁶)R³⁷ and

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R²⁵ is NHC₁-C₄alkyl substituted with one of OH and CH₃.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein R²⁵ is C₁-C₄alkyl is substituted with one of C(O)NHCH₂CH₂OH and OH.

Additional illustrative embodiments of the invention are compounds of Formula (I) selected from the group consisting of

-   3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid -   (*S)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (R)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methy-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,3′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6     (7H)-yl)methyl)-4-methylphenyl)propanoic acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)     3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepin]-4,1′-cyclopropan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl]-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-Chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxyethyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxypropyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-Hydroxy-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((3-Methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Hydroxypropyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-(3-Hydroxyethyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-((7′-((2-morpholinoethyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethyl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(Butylamino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((R)-3-Hydroxy-3-methylbutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((1s,3S)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(3-((2-Hydroxy     ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (3*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (3*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; -   (3*R)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; and -   (3*S)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

Additional illustrative embodiments of the invention are compounds of Formula (I) selected from the group consisting of

-   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid     (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methy-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methy-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methy-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)     3-(3-((7′-(3-Hydroxypropoxy)-1′,1′dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; -   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyri     do[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)     2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts, thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,3′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6     (7H)-yl)methyl)-4-methylphenyl)propanoic acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)     3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepin]-4,1′-cyclopropan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl]-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-Chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxyethyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((2-Hydroxypropyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-Hydroxy-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((3-Methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Hydroxypropyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(−3-((7′-((3-Hydroxyethyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-((7′-((2-morpholinoethyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethyl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(Butylamino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(((R)-3-Hydroxy-3-methylbutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(((1s,3S)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(3-((2-Hydroxyethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (3*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (3*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; -   (3*R)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; and -   (3*S)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (R/S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-m     ethylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-m     ethylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((5)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-[3-[(5,5-Dioxo-7a,8,9,10-tetrahydro-7H-pyrrolo[2,1-d][1,2,5]benzothiadiazepin-6-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic     acid; -   (*R)-3-[3-[(5,5-Dioxo-7a,8,9,10-tetrahydro-7H-pyrrolo[2,1-d][1,2,5]benzothiadiazepin-6-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic     acid; -   (R/S)-3-[3-[(4,4-Dimethyl-1,1-dioxo-3H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic     acid; -   (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Di     oxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic     acid; -   (R/S)-3-(4-Methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-(((S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(t*rifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (3*S)-3-(3-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-4-Ethyl-8-methyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-Chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-2-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-2-Carbamoyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-2-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-2-Carbamoyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (R/S)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3     yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (R/S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; and -   (*R)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-dipyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-b][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*R)-3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic     acid; -   (*S)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-((7′-(3-((2-(2-Aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-((7′-(3-((2-(2-aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′-(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*R)-3-(3-((7′-((2-(4,4-Difluoropiperidin-1-yl)ethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((7′4(1R,3R)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((R-1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′4(S-1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′4(1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b)][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(pyrrolidine-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*R)-3-(3-((1′,1′-Dioxido-7′-((2-(piperazin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-(8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-4-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-1′,1′-Dioxido-7′-(2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   3-(*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-piperidin-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-((7′-(2-(4-Methoxypiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((*R)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dim     ethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-2,2-Dim     ethyl-3-(4-methyl-3-(((*R)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((*R)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*R)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic     acid; -   (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic     acid; -   3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; -   (*S)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic     acid; and

pharmaceutically acceptable salts, and combinations thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is selected from the group consisting of

-   (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; -   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; -   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; -   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; -   and pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyri     do[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is (*S-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

An additional illustrative embodiment of the invention is a compound of Formula (I), wherein the compound is

-   (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic     acid; and

pharmaceutically acceptable salts thereof.

Abbreviations and acronyms used herein include those listed in Table 1.

TABLE 1 Table of Abbreviations Acronym Term Ac Acyl or Acetyl ACN or MeCN Acetonitrile AcOH, HOAc Acetic acid AcOK or KOAc Potassium acetate Ar Argon B₂Pin₂ Bis(pinacolato)diboron HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluoro- phosphate BF₃—Et₂O Boron trifluoride diethyl etherate Boc Tert-butylcarbamoyl Boc₂O Di-tert-butyl dicarbonate br Broad t-BuOK or Potassium tert-butoxide KtOBu CSA Camphorsulfonic acid dccp•2HBF₄ 1,3-Bis(dicyclohexylphosphino)propane bis(tetra- fluoroborate) DBAD Di-tert-butyl azodicarboxylate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIPEA Diisopropylethylamine DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1′-Ferrocenediyl-bis(diphenylphosphine) EtOAc Ethyl acetate EtOH Ethanol ESI Electrospray ionization HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluoro- phosphate, N-[(Dimethylamino)-1H-1,2,3-tri- azolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide Herrmann's trans-Bis(acetato)bis[o-(di-o- catalyst tolylphosphino)benzyl]dipalladium(II) HPLC High-pressure liquid chromatography iPrNH₂ Isopropyl amine Josiphos Pd(0) {(R)-1-[(Sp)-2-(Dicyclohexylphosphino)ferro- pre-catalyst G3 cenyl]ethyldi-tert-butylphosphine}[2-(2′-amino- 1,1′-biphenyl)]palladium(II) methanesulfonate LCMS Liquid chromatography and mass spectrometry LAH Lithium aluminium hydrideabbre LDA Lithium diisopropylamide LG Leaving Group m/z Mass to charge ratio MeOH Methanol MeI Methyl iodide MS Mass spectrometry MTBE Methyl tert-butyl ether NaOAc Sodium acetate NaOMe Sodium methoxide NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance OMs O—CH₃S(O)₂ OTf or triflate CF₃S(O)₂O— OTs O—S(O)₂—p-CH₃—C₆H₅ Pd(t-Bu₃P)₂ Bis(tri-tert-butylphosphine)palladium(0) Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)-ferrocene]di- chloropalladium (II) Pd(dppf)Cl₂—CH₂Cl₂ [1,1′-Bis(diphenylphosphino)-ferrocene]di- chloropalladium(II), complex with dichloro- methane Pd(PPh₃)₂Cl₂ Palladium(II)bis(triphenylphosphine) dichloride Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0) Pd(dtbpf)Cl₂ [1,1′-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) P(1-nap)₃ Tri-1-naphthylphosphine Pd(OAc)₂ Palladium(II) acetate P(o-tol)₃ Tri(o-tolyl)phosphine PG Protecting Group POBr₃ Phosphorus(V) oxybromide [Rh(COD)Cl]₂ Chloro(1,5-cyclooctadiene)rhodium(I) dimer RockPhos Pd G3 [(2-Di-tert-butylphosphino-3-methoxy-6-methyl- 2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-amino- biphenyl)]palladium(II) methanesulfonate SFC Supercritical Fluid Chromatography Me₃Si Trimethylsilyl TMSCN Trimethylsilyl cyanide TBAF Tetra-n-butylammonium fluoride TBAB Tetrabutylammonium bromide TBS Tert-butyldimethylsilyl TBSCl Tert-butyldimethylsilyl chloride TBSOTf Tert-butyldimethylsilyl triflate TEA or Et₃N Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride tosyl p-toluenesulfonyl THF Tetrahydrofuran TLC Thin layer chromatography tol-BINAP 2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl- biphenyl X-Phos Pd G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri- isopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) Zn(CN)₂ Zinc cyanide

Illustrative compounds useful in methods of this invention are described below by reference to the illustrative synthetic schemes (“Schemes”) and specific examples for their preparation. Compounds of Formula (I)

are synthesized in accordance with the Schemes. By way of illustration, but not as a limitation, compounds according to this invention are prepared according to the following general preparation procedures given by Schemes 1-12. One of ordinary skill in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent.

Unless otherwise specified, the variables in Schemes 1-12 are as defined above in reference to Formula (I). The following general features concerning reaction temperatures, protecting groups PG, leaving groups LG, and substituent R³⁵ refer, as applicable, to all the Schemes 1-12.

If no temperature or temperature range is stated, it is to be understood that the reaction is to be run at room temperature.

The term PG in the following schemes represents a protecting group such as an acetyl (Ac), or a t-butyldimethylsilyl (TBS).

The conditions to protect an alcohol as an acetyl include treatment of the alcohol with (i) acetyl chloride in the presence of a base such as triethylamine, DIPEA or pyridine in a reaction medium provided by solvents such as dichloromethane, DMF or THF at a temperature ranging from about 0° C. to about room temperature wherein DMAP may optionally be added, or (ii) acetic anhydride in the presence of a base such as triethylamine, DIPEA or pyridine in a reaction medium provided by solvents such as dichloromethane, DMF or THF at a temperature ranging from about 0° C. to about room temperature, wherein DMAP may optionally be added. These conditions are referred to as “acetyl protection conditions”. The conditions to remove an acetyl group include using a base such as potassium carbonate in a reaction medium provided by solvents such as THF, methanol, ethanol, water, or mixtures thereof. These deprotection conditions are referred to as “acetyl group deprotection conditions”.

Other conditions to protect an alcohol rely on its protection as a TBS ether by coupling the alcohol with TBS-Cl or TBS-OTf in the presence of a base such as imidazole, 2,6-lutidine, triethylamine, DIPEA or pyridine in a reaction medium provided by solvents such as dichloromethane, DMF or THF at a temperature ranging from about 0° C. to about room temperature, wherein DMAP may optionally be added. These conditions are referred to as “TB S protecting group conditions”. The TBS group is removed by (i) TBAF in a solvent such as THF or DMF at a temperature ranging from about 0° C. to about 70° C., or (ii) HCl or CSA in a reaction medium provided by solvents such as THF, ethanol, methanol, water or mixtures thereof at a temperature ranging from about 0° C. to about room temperature. These deprotection conditions are referred to as “TB S group deprotection conditions”.

R³⁵ is defined as C₁-C₄alkyl.

The term LG refers to a leaving group. Examples of leaving groups include I, Cl, Br, OMs and OTs.

When isomerically pure samples are desired, isomeric mixtures of compounds synthesized according to Scheme 1 can be separated by chiral SFC or HPLC.

As shown in Scheme 1, compound II is converted to compound IV by coupling it with one of compounds IIIa′-d′ (HetBH) under Mitsunobu reaction conditions. This Mitsunobu reaction is performed by using diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate in the presence of triphenylphosphine or solid-supported triphenylphosphine in a reaction medium provided by solvents such as THF, DMF, dichloromethane, or mixtures thereof, at a temperature range from about room temperature to about the reflux temperature of the solvent. These conditions are referred to as “Mitsunobu reaction conditions”. Compound IIIa′ is made as shown in Schemes 10a and 12a, compound IIIb′ is made as shown in Schemes 10b and 12b, compound IIIc′ is made as shown in Scheme 10c and compound Hid′ is made as shown in Scheme 10d. Compound V is converted to compound IV by coupling it with one of compounds IIIa′-d′ (HetBH) in an alkylation reaction. This alkylation reaction is performed by using a base such as sodium hydride or potassium tert-butoxide, in a reaction medium provided by solvents such as THF or DMF. Alternatively, compound IV is made as shown in Scheme 3b. Compound IV is converted to compound (I) under hydrolysis reaction conditions, employing an aqueous solution of NaOH or LiOH, in a reaction medium provided by solvents such as water, THF, 1,4-dioxane, methanol, ethanol, or mixtures thereof, at a temperature range from about room temperature to about the reflux temperature of the solvent. These conditions are referred to as “basic hydrolysis reaction conditions” Compound VI (PG is Ac) is converted to compound II under acetyl group deprotection conditions. Alternatively, compound II is made as shown in Scheme 3b. Compound VI (PG is TBS) is converted to compound V by treatment with a chlorinating agent such as thionyl chloride with or without DMF as an additive in a reaction medium provided by solvents such as dichloromethane or dichloroethane, to yield compound V. Compound VI is made as shown in Schemes 2, 3b and 4.

As shown in Scheme 2, compound VIIa is converted to compound VIIb by a two-step process. The first step in this two-step process is reduction of benzoate VIIa to a benzyl alcohol (structure not shown) with a reducing agent such as LiAlH₄ in a reaction medium provided by a solvent such as THF at a temperature ranging from about 0° C. to about 15° C. The second step in this two-step protocol is the protection of the benzyl alcohol as a TBS ether under TBS protection conditions. Compound VIIb is converted to compound IX by initially treating compound VIIB with a reagent such as n-butyllithium at a low temperature such as about 78° C. in a reaction medium provided by a solvent such as THF, forming an organolithium intermediate (structure not shown), this organolithium intermediate is then treated with compound VIIIa (made as shown in Schemes 4 and 9) or VIIIb (made as shown in Scheme 5) to form compound IX. Compound IX is converted to compound VI by coupling with a silylketene acetal X, using trichloroacetonitrile in the presence of the additives DBU and trifluoromethanesulfonamide in a reaction medium provided by a solvent such as acetonitrile, at a temperature ranging from about room temperature to about the reflux temperature of the reaction solvent. Alternatively, this coupling can also be accomplished by using a compound X and a reagent such as BF₃-Et₂O or TiCl₄ in a reaction medium provided by a solvent such as dichloromethane. Compound XIV is also made with a different HetA group as shown in Scheme 8.

As shown in Scheme 3a, HetA-Br (XIa or XIb) is converted to compound XIV by a palladium catalyzed coupling with compound XII with a palladium catalyst such as Pd(dppf)Cl₂ or Pd(dppf)Cl₂.CH₂Cl₂ in the presence of a base additive such as potassium carbonate or sodium carbonate in a reaction medium provided by a solvent such as mixture of 1,4-dioxane and water at a temperature ranging from about room temperature to about the reflux temperature of the solvent. When compound XIII is used, compounds XIa (made as shown in Schemes 6 and 7) or XIb (as made as shown in Scheme 5) are treated with a palladium catalyst such as Herrmann's palladacycle, Pd(dppf)Cl₂, Pd(dtbpf)Cl₂, Pd(PPh₃)₄ or Pd(OAc)₂ in the presence of additives such as tetrabutylammonium chloride hydrate or P(o-tol)₃ and bases such as sodium acetate, triethylamine, diisopropylethyl amine or N,N-dicyclohexylmethyl amine in a reaction medium provided by a solvent such as DMF or DMA, at a temperature ranging from about room temperature to about the reflux temperature of the solvent.

As shown in Scheme 3b, Compound XIV (made as shown in Scheme 3a) is converted into compound II, by coupling it to compound XV, using a rhodium-catalyzed conjugate addition reaction. This conjugate addition reaction is accomplished with a rhodium catalyst such as [Rh(COD)Cl]₂ in the presence of a base such as triethylamine, sodium carbonate, or KOH; in a reaction medium provided by a solvent such as 1,4-dioxane, water, THF, isopropanol, or mixtures thereof; at a temperature ranging from about room temperature to about the reflux temperature of the solvent. These reaction condition are herein referred to as “rhodium-catalyzed conjugate addition reaction conditions”. Compound XIV is converted to compound VI by treating it with compound XVI under rhodium-catalyzed conjugate addition reaction conditions. Compound VIIb is converted to compound XVI by treating it with bis(pinacolato)diboron, a catalyst such as Pd(dppf)Cl₂, an additive such as KOAc in a reaction medium provided by a solvent such as DMF, DMSO, toluene, or 1,4-dioxane at a temperature ranging from about room temperature to about the reflux temperature of the solvent.

As illustrated in Scheme 4, compound XVII is converted to compound XVIII by a three-step process. In the first step, compound XVII is converted into an ester (structure not shown) using a reagent such as thionyl chloride in a reaction medium provided by a solvent such as methanol or ethanol at a temperature ranging from about 0° C. to about 50° C. In the second step, the ester group formed in step one is converted to the corresponding alcohol by reduction (structure not shown) with a reagent such as sodium borohydride in a reaction medium provided by a solvent such as THF at a temperature ranging from about 0° C. to about 30° C. In the third step, the alcohol formed in step two is converted into compound XVIII using acetyl protection conditions. Compound XVIII is converted into compound XIX under Heck reaction conditions using compound XIII, a catalyst such as Pd(OAc)₂, additives such as triethylamine and TBAB, in a reaction medium provided by a solvent such as DMF at a temperature of about 120° C. Compound XIX is converted to compound VI by coupling it with compound XX using rhodium-catalyzed conjugate addition reaction conditions.

As shown in Scheme 5, compound XXI is converted to compound XXII by treatment with aqueous hydrazine at a temperature from about room temperature to about 65° C. Compound XXII is converted to compound XIb by a cyclization reaction with an acid anhydride such as LXXVII. Alternatively, compound XXII is treated with R⁴CO₂H (LXXVIII) in a reaction medium provided by a solvent such as propionic acid at a temperature from about room temperature to about 140° C. to provide XIb. Compound XIb is converted to compound XX by treating with bis(pinacolato)diboron, Pd(dppf)Cl₂, and KOAc in a reaction medium provided by a solvent such as DMF, DMSO, toluene, or 1,4-dioxane, at a temperature of about 70° C. 100° C. Compound XIb is converted to compound XXIII by treatment with potassium vinyltrifluoroborate, a palladium catalyst such as (Ph₃P)₄Pd, Pd(OAc)₂, Pd(dppf)Cl₂ or Pd(dppf)Cl₂.CH₂Cl₂, a base such as K₃PO₄, TEA, K₂CO₃ or NaOAc in a reaction medium provided by a solvent such as a mixture of 1,4-dioxane and water, at a temperature of about 100° C. 110° C. Compound XXIII is converted to compound VIIIb by (i) treatment with ozone in a reaction medium provided by a solvent such as dichloromethane, MeOH, or mixtures thereof, at a temperature of about −78° C. followed by the addition of triphenylphosphine or dimethylsulfide, or (ii) treatment with OsO₄ in a reaction medium provided by a solvent such as mixture of 1,4-dioxane and water, followed by sodium periodate or (iii) treatment with K₂OsO₄.2H₂O in the presence of sodium periodate in a reaction medium provided by a solvent such as mixture of 1,4-dioxane and water.

As depicted in Scheme 6, compound XXIV is converted to compound XXV by treatment with R³⁶-LG (LXXVI), wherein R³⁶ is —C₃-C₄cycloalkyl or —C₁-C₄perhaloalkyl and LG is defined above, in the presence of a base such as cesium hydroxide hydrate or potassium carbonate in a reaction medium provided by a solvent such as DMSO, DMF and water or mixtures thereof at a temperature of about 150° C. Compound XXV is converted to compound XXVI by (i) a halogenation reaction with bromine in the presence of sodium acetate in a reaction medium provided by a solvent such as acetic acid or (ii) with NBS in a reaction medium provided by a solvent such as acetic acid. Compound XXVI is converted to compound XXVII by alkylation of the aniline with R¹-LG (LXXIX), wherein LG is a leaving group as defined above, in the presence of a base such as sodium hydride in a reaction medium provided by a solvent such as DMF. Compound XXVII is converted to compound XXVIII by a reduction of the nitro group with iron or zinc in a reaction medium provided by a solvent such as acetone, ethanol, water, acetic acid, aqueous ammonium chloride solution, or mixtures thereof, at a temperature of about 0° C. to a temperature of about room temperature. Alternatively, this reduction is accomplished by hydrogenation using a catalyst which is a finely grained solid composed mostly of nickel derived from a nickel-aluminum alloy, such as Raney nickel, in a reaction medium provided by a solvent such as ethanol under an atmosphere of hydrogen gas. Compound XXVIII is converted to compound XIa by cyclization with sodium nitrate in the presence of an acid such as aqueous sulfuric acid or aqueous HCl in a reaction medium provided by a solvent such as water, acetic acid, or methanol, or mixture thereof.

As illustrated in Scheme 7, compound XXIX is converted to compound XXV by displacement of the fluorine atom with R¹—NH₂(LXXX); with or without a base such as triethylamine; with or without a reaction medium provided by a solvent such as ethanol or acetonitrile at a temperature ranging between about 50° C. to about 150° C. for an amount of time ranging between 4-48 hours. Compound XXV is converted to compound XIa by a three-step process which includes a bromination reaction, a nitro group reduction reaction, and a cyclization reaction. The conditions for these reactions are as described in Scheme 6 as follows: the bromination reaction conditions are as described in the conversion of XXV to XXVI, the nitro group conditions are as described in the conversion of XXVII to XXVIII and the cyclization reaction conditions are as described in the conversion of XXVIII to XIa. Alternatively, compound XXV is converted to compound XIa using a similar three-step process wherein the order of the reaction steps is a nitro group reduction reaction then a cyclization reaction, followed by a bromination reaction.

As described in Scheme 8, compound L is converted to compound LI by a two-step process. In the first step, the chlorine atom is displaced by R⁹—NH₂ (LXXXI) in a reaction medium provided by a solvent such as methanol at temperature of about 110° C. In the second step, the aniline produced in the first step (structure not shown) is treated with bromine in a reaction medium provided by a solvent such as acetic acid to provide compound LI. Compound LI is converted to compound LII by coupling to 3,3-diethoxyprop-1-yne (structure not shown) using a palladium catalyst such as Pd(PPh₃)₂Cl₂ in the presence of an additives such as CuI and triethylamine at a temperature of about 65° C. for about 1.5 hours. Compound LII is converted to compound LIII by treatment with a reagent such as TBAF in a reaction medium provided by a solvent such as THF at a temperature of about 65° C. Compound LIII is converted to compound LIV using an acid such as HCl in a reaction medium provided by a solvent such as 1,4-dioxane. Compound LIV is converted to compound XIV with a reagent such as ethyl 2-(diethoxyphosphoryl)acetate (structure not shown) using a base such as sodium hydride in a reaction medium provided by a solvent such as THF.

As shown in Scheme 9, compound XIV is converted to compound VIIIa by treatment with ozone in a reaction medium provided by a solvent such as dichloromethane, MeOH, or mixtures thereof, at a temperature of about −78° C. to about 15° C. followed by the addition of triphenylphosphine or dimethyl sulfide.

As depicted in Scheme 10a, compound LVa is converted to compound LVIIa by coupling to an amine reagent LVIa using a base such as potassium carbonate in a reaction medium provided by mixture of solvents such as THF and water. These conditions are referred to as “sulfonamide forming reaction conditions”. Compound LVIIa is converted to compounds IIIa′ via a two-step process. The first step of this two-step process is removal of the tert-butyl carboxy protecting group to produce the free amine (free amine structure not shown). In this first step compound LVIIa is treated with TFA in a reaction medium provided by a solvent such as dichloromethane. These conditions are referred to as “tert-butyl carboxy protecting group removal conditions”. In the second step of this two-step process, the free amine produced in step one is cyclized to IIIa′ by treating with a base such as triethylamine or DIPEA at a temperature ranging from about reflux temperature of THF or toluene to about 160° C. in a reaction medium provided by a solvent such as toluene, DMSO, or THF. These conditions are referred to as “base cyclization conditions”. When this reaction is conducted with compound LVIa wherein Z is N-Cbz, then the Cbz group of compound IIIa′ can be removed using hydrogenolysis conditions such as Pd(OH)₂/C under H₂ in a solvent such as MeOH from a temperature ranging from about room temperature to about 50° C. These conditions are referred to as “Cbz protecting group removal conditions”. The free amine that is produced from this Cbz removal can then be methylated by treatment with 37% aqueous HCHO and NaBH₃CN in a solvent mixture such as MeOH:DCM (2:1) at a temperature range of about room temperature to about 50° C. to provide compound IIIa′ wherein Z is NMe.

As depicted in Scheme 10b, compound LVb is converted to compound LVIIb by coupling to an amine reagent LVIb (made as shown in Scheme 11) using sulfonamide forming reaction conditions. Compound LVIIb is converted to compound IIIb via a two-step process. In this first step, compound LVIIb is subjected to tert-butyl carboxy protecting group removal conditions. In the second step of this two-step process, the free amine produced in step one is cyclized to IIIb′ using base cyclization conditions.

As depicted in Scheme 10c, compound LVc is converted to compound LVIIc by coupling to an amine reagent LVIc using sulfonamide forming reaction conditions. Compound LVIIc is converted to compound IIIc′ by treating with a base such as potassium carbonate or potassium tert-butoxide in a reaction medium provided by a solvent such as DMSO or water, or mixtures thereof, at a temperature range of about 80° C. to about 110° C. for a time range between 2-40 hours. These conditions are referred to as “alternative base cyclization conditions”. In amine reagent, LVIc, when R²² and R²³ are taken together with the carbon to which they are attached to form an azetidine, pyrrolidine or piperidine, the nitrogen atom of the azetidine, pyrrolidine or piperidine is protected with a protecting group such as tert-butyl carboxy group. This protecting group could then be removed after compound IIIc′ has been formed using “tert-butyl carboxy protecting group removal conditions”.

As depicted in Scheme 10d, compound LVd is converted to compound LVIId by coupling to an amine reagent LVId using sulfonamide forming reaction conditions. Compound LVII is converted to compound III′ using alternative base cyclization conditions.

As depicted in Scheme 10e, compound LVd is converted to compound CXX by coupling to an amine reagent XXXe using sulfonamide forming reaction conditions. Compound CXX is converted to compound CXXI by removal of the protecting group (PG) using Cbz protecting group removal conditions when PG is Cbz. Compound CXXI is converted to compound III'd using alternative base cyclization conditions.

As described in Scheme 11, compound LX is converted to compound LXI by treating compound LX with a base such as LDA in a reaction medium provided by a solvent such as THF, ether, hexanes, toluene, and mixtures thereof and then adding an alkyl halide reagent R²⁰-LG (LXXXII). Compound LXI is converted to compound LVIb using a catalyst which is a finely grained solid composed mostly of nickel derived from a nickel-aluminum alloy, such as Raney nickel, in a reaction medium provided by a solvent mixture such as methanol and aqueous ammonia, under a hydrogen atmosphere.

As shown in Scheme 12a, compound LXX is converted to compound LXXI by treating with HBF₄ and tert-butyl nitrite in a reaction medium provided by a solvent such as acetonitrile at a temperature of about 0° C. Compound LXXI, shown in brackets above, is not isolated, and is converted to compound LXXII by adding the reaction solution containing LXXI to a separate solution of CuCl in a reaction medium provided by a solvent such as acetic acid which is saturated by bubbling with SO₂ gas. Compound LXXII is converted to compound LXXXIV using a two-step process wherein compound LXXII is coupled with compound LVIa using sulfonamide forming reaction conditions. This product is then subjected to tert-butyl carboxy protecting group removal conditions to provide compound LXXXIV. Compound LXXXIV is converted to compound LXXIII using base catalyzed cyclization condition or alternative base catalyzed cyclization condition. Compound LXXIII is converted to compounds IIIa′, wherein R²⁶ is —CN, by a palladium-catalyzed cyanation reaction. This cyanation reaction is achieved by using a palladium catalyst such as Pd(dppf)Cl₂ or Pd₂(dba)₃, using zinc cyanide, zinc as an additive, and with or without X-Phos added, in a reaction medium provided by a solvent such as DMF or DMA, at a temperature of about 110° C. to about 140° C. for a time range of 3-16 hours. These conditions are referred to as “palladium-catalyzed cyanation reaction conditions”.

As shown in Scheme 12b, compound LXXIV is converted to compound LXXXIII using a two-step process wherein compound LXXIV is coupled with compound LVIb (made as shown in Scheme 11) using sulfonamide forming reaction conditions. This product is then subjected to tert-butyl carboxy protecting group removal conditions to provide compound LXXXIII. Compound LXXXIII is converted to compound LXXV using base catalyzed cyclization condition or alternative base catalyzed cyclization condition. Compound LXXV is converted to compound IIIb′, wherein R¹⁸ is —CN, using palladium-catalyzed cyanation reaction conditions.

As shown in Scheme 13, compound XC is converted to compound XCI by subjecting it to acidic hydrolysis conditions such as aqueous HCl in a reaction medium provided by solvents such as water, dioxane, THF or mixtures thereof at a temperature range from about room temperature to about reflux temperature of the solvent. Compound XCI is converted to compound XCII under carbonylation conditions, employing a catalyst such as Pd(OAc)₂, an additive such as dccp.2HBF₄ in the presence of a base such as K₂CO₃ in a reaction medium provided by a solvent such as MeOH at a temperature range from about room temperature to about reflux temperature of the solvent under an atmosphere of CO at a pressure range of about 15 psi to about 50 psi. Compound XCII is converted to XCIII by treating it with POBr₃ in a reaction medium provided by a solvent such as toluene at a temperature range from about room temperature to about reflux temperature of the solvent. Compound XCIII is converted to compound XCIV by reduction with a reagent such as sodium borohydride in a reaction medium provided by a solvent such as THF at a temperature ranging from about 0° C. to about 30° C. Compound XCIV is converted to compound XCV by subjecting it to TBS protecting group conditions.

As shown in Scheme 14, compound XCVI is converted to compound XCVII by reduction with a reagent such as sodium borohydride in a reaction medium provided by a solvent such as THF at a temperature ranging from about 0° C. to about 30° C. Compound XCVII is converted to compound XCVIII subjecting XCVII to TBS protecting group conditions.

As shown in Scheme 15, compound XVII is converted to compound XCIX using thionyl chloride in a reaction medium provided by a solvent such as methanol at a temperature ranging from about 0° C. to about 50° C. XCIX is converted to compound C by reduction with a reagent such as sodium borohydride in a reaction medium provided by a solvent such as THF at a temperature ranging from about 0° C. to about 30° C. Compound C is converted to compound CI by subjecting C to TBS protecting group conditions. Compound CI is converted to compound CII under carbonylation conditions, employing a catalyst such as Pd(dppf)₂Cl₂ in the presence of a base such as TEA in a reaction medium provided by solvents such as MeOH, DMF or mixtures thereof at a temperature range from about room temperature to about 100° C. under an atmosphere of CO at a pressure range of about 15 psi to about 50 psi. Compound CII is converted to CIII by treating with DIBAL-H in a reaction medium provided by a solvent such as dichloromethane at a temperature ranging from about −78° C. to about −50° C.

As shown in Scheme 16, compound CVIII is prepared from compound CIV through several different pathways depending on the conditions used and on the choice of the R²⁴ substituent. For example, compound CIV is converted to compound CV through a two-step reaction. In the first step, compound XXXa or XXXb is treated with tBuOK or NaH in a reaction medium provided by a solvent such as t-butanol when using tBuOK or THF when using NaH.

The product from this first step is then added to a solution of compound CIV in a in a reaction medium provided by solvent such as DMSO at a temperature ranging from about room temperature to about 100° C. Alternatively, compound CIV is converted to compound CV through a different two-step process. In the first step, compound XXXa or XXXb is treated with tBuOK or NaH in a reaction medium provided by a solvent such as t-butanol when using tBuOK or THF when using NaH. The product from this first step is then added to a solution of compound CIV in a solvent medium such as toluene under palladium catalysis conditions using reagents such as NaH, Pd₂dba₃, racemic 2-(di-t-butylphosphino)-1,1′-binaphthyl, at a temperature ranging from about room temperature to about reflux temperature of solvent. Alternatively, compound CIV is converted to compound CV by treating compound CIV with compound XXXc or XXXd in a reaction medium provided by a solvent such as DMSO at a temperature ranging from about room temperature to about 100° C. Compound CV is converted to compound CVII by coupling it with compound II under Mitsunobu reaction conditions. Alternatively, compound CV is converted to compound CVII by coupling with compound V in an alkylation reaction. This alkylation reaction is performed by treating compound CV with a base such as sodium hydride, potassium tert-butoxide or K₂CO₃, in a reaction medium provided by solvents such as THF, DMF, CH₃CN or mixtures thereof. Compound V is then added to this mixture to provide compound CVII. These conditions are referred to as “alkylation reaction conditions”. Compound CIV is converted to compound CVI by coupling it with II under Mitsunobu reaction conditions. Alternatively, compound CIV is converted to compound CVI by coupling with compound V under alkylation reaction conditions. Compound CVI is converted to CVII using conditions described above for conversion of compound CIV to compound CV. Compound CVII is converted to compound CVIII under basic hydrolysis reaction conditions. Alternatively, the hydrolysis is also performed under acidic conditions using TFA in a reaction medium provided by solvent such as DCM at a temperature range from about room temperature to about the reflux temperature of the solvent. These conditions are referred to as “acidic hydrolysis conditions”. In instances where the R³⁵ is Bn, hydrogenation conditions are employed for removal of the benzyl group such as transfer hydrogenation conditions using Pd/C as the catalyst and cyclohexadiene in a reaction medium provided by a solvent such as ethanol at a temperature range of about room temperature to about reflux temperature of the solvent. Alternatively, the benzyl group is removed using 10% Pd(OH)₂/C or 10% Pd/C in a reaction medium such as methanol as the solvent at a temperature range of about room temperature to about 50° C. under an atmosphere of H² gas wherein the reaction may be conducted in a conventional reaction flask or using a continuous flow hydrogenation reactor. The above conditions to remove a benzyl group are referred to as “benzyl deprotection conditions”. When compounds XXXb and XXXc are used, the protecting group, PG, is removed using TBS deprotection conditions when PG is TBS or benzyl protecting group conditions when PG is benzyl.

As shown in Scheme 19, compound CVIII is prepared from compound CIV by a pathway that proceeds through key intermediates CXX and CXXI. Compound CIV is transformed into compound CXX by a two-step sequence. In the first step, using Heck reaction conditions, compound CIV where R²⁹ is halo is converted to compound CIV where R²⁹ is (CH₃)₃(C)C(O)CH═CH (structure not shown), using tert-butyl acrylate, a catalyst such as palladium acetate, additives such as triethylamine and 2-(di-tert-butylphosphino)biphenyl, in a reaction medium provided by a solvent such as DMF at a temperature of about 120° C. In the second step, compound CIV where R²⁹ is (CH₃)₃(C)C(O)CH═CH— is reduced to compound CIV where R²⁹ is (CH₃)₃(C)C(O)CH₂CH₂ (Compound CXX) under an atmosphere of hydrogen gas, at a pressure of about 50 psi, using a catalyst such as palladium on carbon, in a reaction medium provided by a solvent such as methanol at a temperature of about room temperature. Compound CXX is transformed into compound CXXI by a two-step sequence. In the first step, compound CXX and compound II (shown in Scheme 1) are coupled under Mitsunobu reaction conditions as described above in Scheme 1. In the second step, the tert-butyl carboxy protecting group is removed under reaction conditions described above in Scheme 10a. Compound CXXI is transformed into compound CVIII by either a two-step reaction sequence or a three-step reaction sequence depending on the R²⁴ substituent. If the R²⁴ substituent contains a primary amide (substituent AA), a secondary cyclobutyl-substituted amide (substituent BB), or an ethanolamine amide group (substituent CC), then the two-step reaction sequence is used. In the first step of the two-step reaction sequence, an amide bond is formed with the appropriate amine in the presence of additives such as HATU and DIPEA in a reaction medium provided by a solvent such as DMF at a temperature of about room temperature. In the second step of the two-step reaction sequence, the R³⁵ acid protective group is removed under basic hydrolysis conditions (R³⁵=methyl) or under hydrogenation conditions (R³⁵=Bn) as described in Scheme 16. In the instance where the R²⁴ substituent is the N-(2-(2-aminoethoxy)ethyl)propionamide group (substituent DD), the three-step reaction sequence is followed. This three-step reaction sequence consists of the above two-step reaction sequence followed by the addition of a third step wherein the terminal NH₂ of substituent DD is deprotected. The deprotection of the Boc group under the tert-butyl carboxy protecting group removal conditions described in Scheme 10a.

The following examples are provided to further illustrate aspects of the invention and various preferred embodiments.

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Reaction mixtures were magnetically stirred at room temperature. Where solutions are characterized as “dried,” they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography was performed using Merck silica gel 60 F254 2.5 cm×7.5 cm, 250 μm or 5.0 cm×10.0 cm, 250 μm pre-coated silica gel plates.

Normal-phase flash column chromatography was performed on silica gel (SiO₂) eluting with 2 M NH₃ in MeOH/CH₂Cl₂, unless otherwise noted.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.

High Performance Liquid Chromatography was performed as described for the individual compounds. Compound purification was made in some cases by acidic HPLC that entailed purification on a reverse phase HPLC system using different mobile phases that started initially with a mobile phase of 5% ACN in H₂O (both with 0.05% TFA) that was held for 1 min, then changed to a gradient of 5-99% ACN over 6 min, which was held at 99% ACN for 3 min, with a flow rate of 80 mL/min. The following endcapped columns were used: Waters Xbridge Prep OBD C₁₈ (pore size 130 Å, surface area 185 m²/g, carbon load of 18%), Phenomenex Luna C18, (pore size 100 Å, surface area 440 m²/g, carbon load of 19%), Phenomenex Synergi-Max C₁₈ (pore size 100 Å, surface area 475 m²/g, carbon load of 11-19%), SunFire Prep C₁₈ OBD (pore size 100 Å, surface area 340 m²/g, carbon load of 16%), and Phenomenex Gemini (pore size 110 Å, surface area 375 m²/g, carbon load of 14%).

SFC was performed as described for individual compounds using the following stationary phase columns Chiralpak AD-H, Chiralpak IG, Chiralpak IC, Chiralpak AS-H, Chiralcel OJ-H, Chiralcel OZ-H, Phenomenex cellulose-2, Whelk O1 (S,S). The mobile phases used are described in the individual experimental write ups and usually consisted of varying amounts of CO₂ and alcoholic solvents such as methanol, ethanol, isopropanol, EtOH/H₂O containing 0.1% NH₃.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the ¹H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference or to residual protium in the solvent (multiplicity, coupling constant J in Hz, integration).

Chemical names were generated by either using ChemDraw (CambridgeSoft, Cambridge, Mass.) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value.

Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Reagent concentrations that are given as percentages refer to mass ratios, unless indicated differently.

Intermediate 1: 7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl 2-((2-chloropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate. K₂CO₃ (22.6 g, 163 mmol) was added to a mixture of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (50.08 g, 233.7 mmol), in THF (525 mL) and H₂O (105 mL). 2-Chloropyridine-3-sulfonyl chloride (33.0 g, 156 mmol) was then added and the mixture was stirred at room temperature for 6.5 hours. The mixture was concentrated to dryness under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous MgSO₄, filtered and concentrated to dryness under reduced pressure and purified by flash column chromatography (eluent: hexanes/ethyl acetate, 1:0 to 1:1, gradient elution) to afford the title compound (60 g, 99%) as a white solid. MS (ESI): mass calcd. for C₁₆H₂₄ClN₃O₄S, 389.1; m/z found, 290.1 [M-BOC+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (dd, J=4.8, 1.9 Hz, 1H), 8.40 (dd, J=7.8, 1.9 Hz, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 5.73 (s, 1H), 4.38 (dt, J=10.2, 5.5 Hz, 1H), 3.93 (d, J=14.2 Hz, 1H), 3.34 (s, 1H), 2.93 (dt, J=12.3, 5.1 Hz, 1H), 2.74-2.69 (m, 1H), 2.05 (s, 1H), 1.62-1.52 (m, 3H), 1.48 (s, 9H), 1.39 (tdd, J=10.1, 4.8, 2.5 Hz, 2H).

Step B: 7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. A solution of 20% TFA in DCM (165 mL, 2.15 mol) was added to tert-butyl 2-((2-chloropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate (55.0 g, 141 mmol). The resulting mixture was stirred for 2.5 hours at room temperature, concentrated to dryness under reduced pressure and re-dissolved in toluene (645 mL). TEA (119.1 mL, 857.2 mmol) was added and the resulting mixture was heated to reflux for 15 hours, cooled to room temperature, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: hexanes/ethyl acetate, 1:0 to 0:1, gradient elution) to afford the title compound (31 g, 82% (95% purity)). MS (ESI): mass calcd. for C₁₁H₁₅N₃O₂S, 253.1; m/z found, 254.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.24 (dd, J=4.7, 1.9 Hz, 1H), 7.92 (dd, J=7.8, 1.8 Hz, 1H), 6.77 (dd, J=7.8, 4.6 Hz, 1H), 5.30 (s, 1H), 4.36-4.20 (m, 2H), 3.49 (t, J=12.7 Hz, 1H), 3.44-3.31 (m, 2H), 1.84-1.74 (m, 3H), 1.71-1.55 (m, 3H).

Intermediate 2: (*S)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

The racemic mixture of 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide enantiomers (Intermediate 1, 31 g) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting isomer (14.6 g) was designated (*S). MS (ESI): mass calcd. for C₁₁H₁₅N₃O₂S, 253.1; m/z found, 254.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.25 (dd, J=4.6, 1.8 Hz, 1H), 7.93 (dd, J=7.8, 1.8 Hz, 1H), 6.77 (dd, J=7.8, 4.6 Hz, 1H), 5.24 (t, J=6.0 Hz, 1H), 4.37-4.28 (m, 1H), 4.24 (dt, J=13.3, 4.9 Hz, 1H), 3.50 (ddd, J=13.4, 11.9, 6.4 Hz, 1H), 3.47-3.32 (m, 2H), 1.87-1.75 (m, 3H), 1.72-1.56 (m, 3H).

Intermediate 3: (*R)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer from the separation of isomers by chiral SFC described in Intermediate 2 (15.2 g) was designated (*R). MS (ESI): mass calcd. for C₁₁H₁₅N₃O₂S, 253.1; m/z found, 254.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (dd, J=4.7, 1.9 Hz, 1H), 7.90 (dd, J=7.8, 1.8 Hz, 1H), 6.75 (dd, J=7.8, 4.6 Hz, 1H), 5.42 (t, J=5.9 Hz, 1H), 4.31 (dq, J=12.0, 4.7 Hz, 1H), 4.23 (dt, J=13.3, 4.8 Hz, 1H), 3.50 (ddd, J=13.5, 12.0, 6.4 Hz, 1H), 3.47-3.31 (m, 2H), 1.85-1.73 (m, 3H), 1.69-1.55 (m, 3H).

Intermediate 4: (R)-6,7,7a,8,9,10-Hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl (R)-2-(((2-chloropyridine)-3-sulfonamido)methyl)pyrrolidine-1-carboxylate. Water (17 mL) was added to a solution of tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate (7.50 g, 37.4 mmol) in THF. K₂CO₃ (3.67 g, 26.6 mmol) and 2-chloropyridine-3-sulfonyl chloride (5.25 g, 24.8 mmol) were sequentially added and the resulting mixture was stirred at room temperature for 2 hours. THF was removed under reduced pressure and the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over anhydrous MgSO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0 to 20% EtOAc/DCM, gradient elution) to afford the title compound (8.9 g, 95%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (dd, J=4.8, 1.8 Hz, 1H), 8.39-8.26 (m, 2H), 7.66 (dd, J=7.8, 4.8 Hz, 1H), 3.74-3.51 (m, 1H), 3.12 (t, J=14.1 Hz, 3H), 2.93-2.78 (m, 1H), 1.94-1.63 (m, 4H), 1.36 (s, 9H).

Step B: (R)-6,7,7a,8,9,10-Hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. TFA in DCM (1:4 v/v, 80 mL) was added to tert-butyl (R)-2-(((2-chloropyridine)-3-sulfonamido)methyl)pyrrolidine-1-carboxylate (8.50 g, 22.6 mmol) at room temperature. The resulting mixture was stirred for 1 hour and the solvents were removed under reduced pressure. THF (80 mL) and TEA (20 mL, 143.8 mmol) were added and the resulting mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. Ethyl acetate was added to the residue. The resulting solution was washed with brine, dried over anhydrous MgSO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0 to 30% EtOAc/DCM, gradient elution) to afford the title compound (4.7 g, 86%). MS (ESI): mass calcd. for C₁₀H₁₃N₃O₂S, 239.1; m/z found, 240.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.27 (dd, J=4.7, 1.8 Hz, 1H), 8.06 (s, 1H), 7.94 (dd, J=7.7, 1.8 Hz, 1H), 6.85 (dd, J=7.7, 4.7 Hz, 1H), 4.25-4.15 (m, 1H), 3.66-3.56 (m, 1H), 3.56-3.48 (m, 1H), 3.29 (dd, J=13.2, 3.4 Hz, 1H), 3.03 (dd, J=13.2, 11.9 Hz, 1H), 2.15-2.02 (m, 1H), 1.94-1.84 (m, 2H), 1.74-1.65 (m, 1H).

Intermediate 5: 2′,3′-Dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2-Chloro-N-((1-hydroxycyclopropyl)methyl)pyridine-3-sulfonamide. A solution of 2-chloropyridine-3-sulfonyl chloride (13.0 g, 61.3 mmol) in THF (30 mL) was added dropwise to a mixture of 1-(aminomethyl)cyclopropanol (5.0 g, 57 mmol), K₂CO₃ (15.0 g, 109 mmol), THF (20 mL), and H₂O (10 mL) at 0° C. The resulting mixture was stirred for 12 hours with gradual warming to room temperature before concentrating to dryness under reduced pressure. The residue was diluted with water (150 mL) and the aqueous layer was extracted with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure to afford the title compound (10 g) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C₉H₁₁ClN₂O₃S, 262.0; m/z found, 262.8 [M+H]⁺.

Step B: 2′,3′-Dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. t-BuOK (10 g, 89 mmol) was added in portions to a solution of 2-chloro-N-((1-hydroxycyclopropyl)methyl)pyridine-3-sulfonamide (10 g) in DMSO (50 mL) at 0° C. The resulting mixture was heated to 80° C. for 4 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (100 mL), and the pH adjusted to pH 6 with 1 N aqueous HCl. The aqueous layer was extracted with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 1:4, gradient elution) to afford the title compound (4.3 g, 47%) as a yellow solid. MS (ESI): mass calcd. for C₉H₁₀N₂O₃S, 226.0; m/z found, 227.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.35 (m, 1H), 8.24-8.13 (m, 2H), 7.42-7.37 (m, 1H), 3.54-3.43 (m, 2H), 0.91-0.84 (m, 2H), 0.77-0.70 (m, 2H).

Intermediate 6: 8′-Methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2-Chloro-N-((l-hydroxycyclopropyl)methyl)-5-methylpyridine-3-sulfonamide. 2-Chloro-5-methylpyridine-3-sulfonyl chloride (89.0 g, 394 mmol) in THF (300 mL) was added dropwise to a mixture of 1-(aminomethyl)cyclopropanol (68.5 g, 413 mmol) and K₂CO₃ (136 g, 984 mmol) in THF (1.3 L) and H₂O (400 mL) while keeping the inner temperature around 0˜5° C. The reaction mixture was allowed to warm to room temperature and stirred at 25° C. for 16 hours. The reaction mixture was diluted with water (500 mL) and the aqueous layer was extracted with ethyl acetate (500 mL×1, 300 mL×2). These extractions resulted in several organic solvent fractions which were combined, washed with brine (800 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate/ethanol, 9:3:1 to 3:1:0, gradient elution), followed by trituration in MTBE (120 mL) to afford the title compound (42 g, 39%). MS (ESI): mass calcd. for C₁₀H₁₃ClN₂O₃S, 276.1; m/z found, 276.8 [M+H]⁺.

Step B: 8′-Methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. An aqueous solution of K₂CO₃ (3 M, 152 mL) was added to a mixture of 2-chloro-N-((1-hydroxycyclopropyl)methyl)-5-methylpyridine-3-sulfonamide (42.0 g, 152 mmol) in DMSO (800 mL) and the solution was stirred at 95° C. for 40 hours under Na. A black brown suspension was obtained. The mixture was diluted with H₂O (1.5 L) and 4 N HCl in MeOH was added to the solution until the pH was 7. The aqueous layer was extracted with EtOAc (1 L and then 500 mL×6). These extractions resulted in several organic solvent fractions which were combined, washed with brine (1 L), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:1 to 1:4, gradient elution) and triturated in MTBE (100 mL) for 0.5 hours to afford the title compound (21.5 g, 59%). MS (ESI): mass calcd. for C₁₀H₁₂N₂O₃S, 240.1; m/z found, 241.3. [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=1.8 Hz, 1H) 8.13 (br s, 1H) 8.05 (d, J=2.0 Hz, 1H) 3.49 (s, 2H) 2.34 (s, 3H) 0.86-0.93 (m, 2H) 0.69-0.79 (m, 2H).

Intermediate 7: 2,3-Dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide

Step A: 2-Fluoro-N-((3-hydroxyoxetan-3-yl)methyl)benzenesulfonamide. A mixture of 3-(aminomethyl)oxetan-3-ol (30.0 g, 291 mmol), 2-fluorobenzene-1-sulfonyl chloride (38.0 g, 195 mmol), K₂CO₃ (23.0 g, 217 mmol), THF (240 mL) and H₂O (60 mL) were stirred at room-temperature for 2.5 hours. The reaction mixture was poured into H₂O (50 mL) and extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (20 mL), dried over anhydrous MgSO₄, filtered and concentrated to dryness under reduced pressure to afford the title compound (40 g) which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₀H₁₂FNO₄S, 261.1; m/z found, 262.2 [M+H]⁺.

Step B: 2,3-Dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane]1,1-dioxide. A mixture of 2-fluoro-N-((3-hydroxyoxetan-3-yl)methyl)benzenesulfonamide (40 g), t-BuOK (47.0 g, 419 mmol), and DMSO (150 mL) was sparged with Na for 5 minutes and was stirred at 95° C. for 4 hours. The reaction mixture was cooled to room temperature, acidified to pH 2 with 5 N aqueous HCl, and poured into H₂O (50 mL). The resulting suspension was filtered and washed with H₂O (30 mL) and petroleum ether (20 mL). The solid was triturated with petroleum ether/ethyl acetate (4:1, 50 mL) and filtered, dried under reduced pressure to afford the title compound (23.6 g, 62%) as a yellow solid. To obtain a second portion of the title compound, the filtrate was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous MgSO₄, filtered and concentrated to dryness under reduced pressure to give a second portion of the title compound, which was purified by preparative HPLC using a Phenomenex Synergi Max-RP, 250×50 mm×10 μm column (eluent: 10% to 40% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to afford pure product. The product was suspended in water (20 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (6.35 g) as a yellow solid. Total compound obtained from this experiment was 30.0 g. LC-MS (ESI): RT=3.27 min, mass calcd. for C₁₀H₁₁NO₄S 241.0, m/z found 242.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (t, J=6.7 Hz, 1H), 7.71 (dd, J=7.8, 1.7 Hz, 1H), 7.61 (dt, J=7.8, 1.7 Hz, 1H), 7.44-7.40 (m, 1H), 7.35-7.30 (m, 1H), 4.43 (d, J=7.3 Hz, 2H), 4.33 (d, J=7.5 Hz, 2H), 3.74 (d, J=6.6 Hz, 2H).

Intermediate 8: 7a-Methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl 2-cyano-2-methylpyrrolidine-1-carboxylate. n-BuLi (20 mL, 2.5 M in n-hexane, 50 mmol) was added dropwise to a solution of diisopropylamine (8.6 mL, 61 mmol) and THF (120 mL) at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes and was added dropwise to a solution of tert-butyl 2-cyanopyrrolidine-1-carboxylate (8.0 g, 41 mmol) in THF (150 mL) at −78° C. The resulting mixture was stirred at −78° C. for 2 hours and then it was treated with MeI (5.0 mL, 80 mmol). This mixture was stirred at 0° C. for 2 hours before it was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 50:1 to 5:1, gradient elution) to afford the title compound (5 g, 58%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.59 (br s, 1H), 3.48-3.36 (m, 1H), 2.58-2.45 (m, 1H), 2.04-1.85 (m, 3H), 1.70 (br s, 3H), 1.52 (br s, 9H).

Step B: tert-Butyl 2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate. Raney Ni (1 g) was added to a mixture of tert-butyl 2-cyano-2-methylpyrrolidine-1-carboxylate (1.0 g, 4.8 mmol), methanol (20 mL), and 25% aqueous NH₃ (5 mL) under Ar. The resulting mixture was stirred under H₂ (15 psi) at room temperature for 2 hours. The suspension was filtered through diatomaceous earth such as Celite® and the filtrate was concentrated to dryness under reduced pressure to afford the title compound (750 mg, 74%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.61 (d, J=5.1 Hz, 1H), 3.41-3.28 (m, 1H), 3.23 (d, J=13.0 Hz, 1H), 3.08 (d, J=13.0 Hz, 1H), 2.72-2.59 (m, 1H), 2.12-1.96 (m, 1H), 1.69-1.54 (m, 2H), 1.47 (d, J=13.9 Hz, 12H).

Step C: tert-Butyl 2-((2-chloropyridine-3-sulfonamido)methyl)-2-methylpyrrolidine-1-carboxylate. 2-Chloropyridine-3-sulfonyl chloride (3.5 g, 16 mmol) was added in portions to a mixture of tert-butyl 2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate (3.6 g, 17 mmol), K₂CO₃ (2.74 g, 20.0 mmol) in THF (60 mL) and H₂O (15 mL). The resulting mixture was stirred at room temperature for 16 hours before diluting with H₂O (25 mL) and extracting the aqueous layer with ethyl acetate (50 mL×2). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 5:1, gradient elution) to afford the title compound (5.5 g, 85%). MS (ESI): mass calcd. for C₁₆H₂₄ClN₃O₄S, 389.1; m/z found, 412.0 [M+Na]⁺.

Step D: 2-Chloro-N-((2-methylpyrrolidin-2-yl)methyl)pyridine-3-sulfonamide. TFA (6.5 mL, 85 mmol) was added to a solution of tert-butyl 2-((2-chloropyridine-3-sulfonamido)methyl)-2-methylpyrrolidine-1-carboxylate (5.5 g, 14 mmol) in dichloromethane (20 mL). The resulting mixture was stirred at room temperature for 5 hours and concentrated to dryness under reduced pressure to afford the title compound (4 g) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₁H₁₆ClN₃O₂S, 289.1; m/z found, 289.9 [M+H]⁺.

Step E: 7a-Methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. DIPEA (9.1 mL, 55 mmol) was added to a solution of 2-chloro-N-((2-methylpyrrolidin-2-yl)methyl)pyridine-3-sulfonamide (4.0 g, 14 mmol) and DMSO (30 mL). The resulting mixture was stirred at 160° C. for 6 hours before cooling to room temperature and concentrating to dryness under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and the resulting mixture was washed with H₂O (100 mL×3). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC using a Phenomenex Gemini column, 150×25 mm×5 μm (eluent: 15% to 35% (v/v) CH₃CN and H₂O with 0.05% NH₃) to afford the title compound. The product was suspended in water (50 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (2.9 g, 82%). MS (ESI): mass calcd. for C₁₁H₁₅N₃O₂S, 253.1; m/z found, 254.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39-8.32 (m, 1H), 8.04-7.99 (m, 1H), 7.98-7.92 (m, 1H), 7.02-6.96 (m, 1H), 3.92-3.82 (m, 1H), 3.31-3.20 (m, 2H), 3.17-3.08 (m, 1H), 2.01-1.68 (m, 4H), 0.78 (s, 3H).

Intermediate 9: 7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide

Step A: 5-Bromo-2-chloropyridine-3-sulfonyl chloride. HBF₄ (29.0 mL, 189 mmol) was added dropwise to a solution of 5-bromo-2-chloropyridin-3-amine (25.0 g, 121 mmol) in acetonitrile (200 mL) and the temperature of the solution was kept between 0° C. to 5° C. The resulting mixture was stirred at 0° C. for 10 minutes before adding tert-butyl nitrite (22.0 mL, 185 mmol) dropwise under an atmosphere of N₂. The resulting mixture was stirred at 0° C. for another 2 hours to afford solution one. While solution one was stirring, a separate second solution was prepared wherein a mixture of copper (I) chloride (18.0 g, 182 mmol) and acetic acid (200 mL) was cooled to 0° C., and SO₂ gas was bubbled through the solution (>1.3 M) for 1 hour. Solution one was then added dropwise to solution two at 0° C. under N₂ atmosphere. The resulting mixture was stirred for 16 hours with gradual warming to room temperature. The suspension was filtered and washed with ethyl acetate (30 mL×2). The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether) to afford the title compound (24.5 g, 71%) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=2.6 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H).

Step B: tert-Butyl 2-(((5-bromo-2-chloropyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate. tert-Butyl 2-(aminomethyl)piperidine-1-carboxylate (18.1 g, 84.5 mmol) was added to a suspension of K₂CO₃ (34.9 g, 253 mmol) in THF (150 mL) and H₂O (30 mL) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C. and then treated with 5-bromo-2-chloropyridine-3-sulfonyl chloride (24.5 g, 84.2 mmol). The resulting mixture was stirred at 0° C. for 2.5 hours and concentrated to dryness under reduced pressure. The residue was dissolved in water (50 mL) and the aqueous layer was extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 7:3, gradient elution) to afford the title compound (31 g, 74%) as a yellow solid. MS (ESI): mass calcd. for C₁₆H₂₃BrClN₃O₄S, 467.0; m/z found, 490.1 [M+Na]⁺.

Step C: 5-Bromo-2-chloro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide. TFA (69.0 mL, 995 mmol) was added dropwise to a solution of tert-butyl 2-((5-bromo-2-chloropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate (31 g, 66 mmol) in dichloromethane (120 mL) at 0° C. The resulting mixture was stirred for 16 hours with gradual warming to room temperature. It was then concentrated to dryness under reduced pressure to afford the title compound (35 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₁H₁₅BrClN₃O₂S, 367.0; m/z found, 367.8 [M+H]⁺.

Step D: 3-Bromo-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. DIPEA (120 mL, 881 mol) was added to a mixture of 5-bromo-2-chloro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide (35 g) in toluene (120 mL). The resulting solution was stirred at 130° C. for 2 hours before cooling to room temperature and concentrating to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 3:1, gradient elution) to afford the title compound (19 g, 96%) as a yellow solid. MS (ESI): mass calcd. for C₁₁H₁₄BrN₃O₂S, 331.0; m/z found, 331.7 [M+H]⁺.

Step E: 7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide. Zn(CN)₂ (16.7 g, 142 mmol) was added to a mixture of 3-bromo-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (23.0 g, 69.2 mmol), Zn (906 mg, 13.9 mmol), and DMF (100 mL). The mixture was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl₂ (5.07 g, 6.93 mmol). The resultant mixture was sparged with Ar for another 5 minutes and then stirred at 140° C. for 3 hours before cooling to room temperature. The reaction mixture was filtered and the solid was rinsed with ethyl acetate (10 mL×2). The filtrate was concentrated to dryness under reduced pressure and purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 1:1) to afford the title compound as a brown solid. MS (ESI): mass calcd. for C₁₂H₁₄N₄O₂S, 278.1; m/z found, 278.9 [M+H]⁺.

Intermediate 10: (*R)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide

The mixture of 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide enantiomers (Intermediate 9, 30.0 g) was separated by chiral SFC (stationary phase: Phenomenex cellulose-2, 10 μm 250×50 mm, Mobile phase: 60% CO₂, 40% EtOH/H₂O with 0.1% NH₃) to provide 2 enantiomers. The first eluting enantiomer (12.9 g) was designated (*R). MS (ESI): mass calcd. for C₁₂H₁₄N₄O₂S, 278.1; m/z found, 279.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.48-8.00 (m, 1H), 4.45-4.33 (m, 2H), 3.54 (t, J=13.0 Hz, 1H), 3.42-3.35 (m, 1H), 3.26 (dd, J=13.6, Hz, 1H), 1.79-1.49 (m, 6H).

Intermediate 11: (*S)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide

The second eluting enantiomer from the separation of isomers by chiral SFC described in Intermediate 10 was designated (*S) (13.1 g, 43%). MS (ESI): mass calcd. for C₁₂H₁₄N₄O₂S, 278.08; m/z found, 279.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=2.0 Hz, 1H), 8.33-8.30 (m, 1H), 8.32 (d, J=2.0 Hz, 1H), 4.44-4.34 (m, 2H), 3.54 (t, J=13.2 Hz, 1H), 3.42-3.35 (m, 1H), 3.26 (dd, J=13.2, 3.6 Hz, 1H), 1.79-1.49 (m, 6H).

Intermediate 12: 6,7,7a,8,10,11-Hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl 4-(((2-chloropyridine)-3-sulfonamido)methyl)-1,3-oxazinane-3-carboxylate. 2-Chloropyridine-3-sulfonyl chloride (8.9 g, 42 mmol) was added to a mixture of tert-butyl 4-(aminomethyl)-1,3-oxazinane-3-carboxylate (10 g, 46 mmol) and potassium carbonate (6.8 g, 49 mmol) in THF (150 mL) at room temperature. After 5 hours, the mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, and filtered. Upon standing a solid crashed out of the filtrate. Ethyl ether was added and the slurry was stirred at room temperature, the solids were filtered off to provide the title compound (16.5 g, 100%) as a solid. MS (ESI): mass calcd. for C₁₅H₂₂ClN₃O₅S, 391.1; m/z found, 292.0 [M-CO₂ ^(t)Bu]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.61-8.55 (m, 1H), 8.45-8.39 (m, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 5.85-5.32 (m, 1H), 4.28-4.04 (m, 1H), 3.92-3.67 (m, 3H), 3.60-3.55 (m, 1H), 3.48-3.40 (m, 1H), 3.23-2.97 (m, 2H), 1.50 (s, 9H).

Step B: 6,7,7a,8,10,11-Hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. Trifluoroacetic acid in DCM (165 mL) was added to tert-butyl 4-(((2-chloropyridine)-3-sulfonamido)methyl)-1,3-oxazinane-3-carboxylate (23 g, 58.7 mmol) at room temperature. After 2.5 hours, the mixture was concentrated under reduced pressure and the residue was dissolved in toluene (270 mL). TEA (50.0 mL, 357 mmol) was added and the reaction mixture was stirred at 130° C. for 15 hours. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% ethyl acetate/hexanes, gradient elution) to provide the title compound (18.0 g) as a white solid. MS (ESI): mass calcd. for C₁₀H₁₃N₃O₃S, 255.3; m/z found, 256.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (dd, J=4.6, 1.8 Hz, 1H), 7.94 (dd, J=7.8, 1.8 Hz, 1H), 6.82 (dd, J=7.9, 4.6 Hz, 1H), 5.46 (t, J=5.7 Hz, 1H), 4.38 (ddt, J=12.0, 4.7, 2.7 Hz, 2H), 4.20-3.98 (m, 1H), 3.89-3.65 (m, 4H), 3.58-3.38 (m, 2H).

Intermediate 13: (*S)-6,7,7a,8,10,11-Hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

The mixture of 6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide enantiomers (Intermediate 12, 18 g) was separated by chiral SFC (stationary phase: Chiralpak AS-H 5 μm 250×20 mm, Mobile phase: 60% CO₂, 40% MeOH) to afford two enantiomers. The first eluting isomer (8.25 g) was designated (*S). MS (ESI): mass calcd. for C₁₀H₁₃N₃O₃S, 255.3; m/z found, 256.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J=4.6, 1.8 Hz, 1H), 7.96 (dd, J=7.8, 1.8 Hz, 1H), 6.84 (dd, J=7.9, 4.6 Hz, 1H), 5.29 (t, J=5.6 Hz, 1H), 4.46-4.37 (m, 2H), 4.05 (dt, J=11.2, 3.7 Hz, 1H), 3.91-3.82 (m, 1H), 3.85-3.76 (m, 2H), 3.74 (dd, J=12.2, 2.0 Hz, 1H), 3.60-3.45 (m, 2H).

Intermediate 14: (*R)-6,7,7a,8,10,11-Hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (8.25 g) from the separation of isomers by chiral SFC described in Intermediate 13 was designated (*R). MS (ESI): mass calcd. for C₁₀H₁₃N₃O₃S, 255.3; m/z found, 256.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J=4.6, 1.8 Hz, 1H), 7.97 (dd, J=7.8, 1.8 Hz, 1H), 6.85 (dd, J=7.8, 4.6 Hz, 1H), 5.23 (t, J=5.6 Hz, 1H), 4.46-4.38 (m, 2H), 4.05 (dt, J=11.3, 3.7 Hz, 1H), 3.92-3.83 (m, 1H), 3.86-3.77 (m, 2H), 3.74 (dd, J=12.2, 2.0 Hz, 1H), 3.60-3.46 (m, 2H).

Intermediate 15: Ethyl (E)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)acrylate

Step A: Methyl 6-chloro-3-methylpicolinate. SOCl₂ (90.1 g, 757.6 mmol) was added to a solution of 6-chloro-3-methylpicolinic acid (65.0 g, 379 mmol) in MeOH (300 mL) at 0° C. The resulting solution was stirred for 15 minutes at 0° C., 0.5 hours at 20-30° C., and 6 hours at 50° C. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (300 mL). The organic fraction was washed with saturated aqueous Na₂CO₃ solution (100 mL×3), brine (300 mL), dried over Na₂SO₄, filtered and concentrated to afford the title compound (133.0 g, 94%) as a yellow oil. ¹H NMR (400 MHz CDCl₃) δ 7.53 (d, J=8.0 Hz, 1H), 7.31 (d, J=12 Hz, 1H), 3.89 (s, 3H), 2.49 (s, 3H).

Step B: 6-Chloro-3-methylpyridin-2-yl)methanol. To a suspension of methyl 6-chloro-3-methylpicolinate (65.0 g, 350 mmol) in THF (300 mL) at 0° C. under N₂, was added NaBH₄ (79.5 g, 2.1 mol) in portions. The resulting mixture was heated to 70° C. and stirred for 20 minutes. The reaction was then cooled to 20-30° C. and MeOH (60.0 mL) was added dropwise over 15 minutes and effervescence was observed. This mixture was stirred at 60° C. for 3 hours. The reaction was then cooled to room temperature, quenched with saturated aqueous NH₄Cl solution (500 mL) and stirred for 1.5 hours. The organic layer was separated and the aqueous layer was extracted with EtOAc (250 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated to afford the title compound (104.0 g, 94%) as a yellow oil. ¹H NMR (400 MHz CDCl₃) δ 7.34 (d, J=8.0 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 4.57 (s, 2H), 2.12 (s, 3H).

Step C: 6-Chloro-3-methylpyridin-2-yl)methyl acetate. Acetyl chloride (213.8 g, 2.09 mol) was added to a solution of 6-chloro-3-methylpyridin-2-yl)methanol (110.0 g, 697.9 mmol) and TEA (353 g, 3.49 mol) in THF (1.0 L) at 0° C. The reaction mixture was stirred for 16 hours and gradually warmed to 40° C. over a period of 24 hours. The mixture was concentrated under reduced pressure and diluted with EtOAc (350 mL). The organic portion was washed with saturated aqueous NaHCO₃ solution (250 mL×3), brine (300 mL×3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 100:1 to 50:1, gradient elution) to afford the title compound (95.0 g, 68%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J=8.0 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 5.10 (s, 2H), 2.28 (s, 3H), 2.07 (s, 3H).

Step D: Ethyl (E)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)acrylate. DMF (500 mL) was added to a suspension of 6-chloro-3-methylpyridin-2-yl)methyl acetate (56.0 g, 280 mmol), ethyl acrylate (112 g, 1.12 mol), TEA (56.77 g, 561.0 mmol), TBAB (78.40 g, 243.2 mmol), DPPF (22.40 g, 40.41 mmol) and Pd(OAc)₂ (9.07 g, 40.4 mmol). The mixture was sparged with N₂ for 10 minutes, heated to 120° C. and stirred at this temperature under N₂ atmosphere for 24 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and the organic portion was washed sequentially with 10% aqueous NaHCO₃ solution (500 mL) and brine (500 mL). The resulting organic portion was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 60:1 to 15:1, gradient elution) to afford the title compound (47 g, 63%) as a green oil. MS (ESI): mass calcd. for C₁₄H₁₇NO₄, 263.1; m/z found, 263.9 [M+H]⁺. ¹H NMR: (400 MHz CDCl₃) δ 7.65 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 6.87 (d, J=16 Hz, 1H), 5.24 (s, 2H), 4.29-4.24 (m, 2H), 2.36 (s, 3H), 2.16 (s, 3H), 1.33 (t, J=8 Hz, 3H).

Intermediate 16: 5-Bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole

Step A: N-Ethyl-3-methyl-2-nitroaniline. Ethylamine (210 mL, 3.22 mol) was added to a solution of 1-fluoro-3-methyl-2-nitrobenzene (50.0 g, 322 mmol) in ethanol (500 mL). The mixture was stirred at 50° C. for 48 hours. The reaction mixture was concentrated under reduced pressure and the red oil residue (57.0 g, 98%) was used in the next step without purification. ¹H NMR: (400 MHz, CDCl₃) δ 7.22 (t, J=8.0 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.52 (d, J=7.4 Hz, 1H), 6.46 (br s, 1H), 3.21-3.30 (m, 2H), 2.48 (s, 3H), 1.28-1.36 (m, 3H).

Step B: 4-Bromo-N-ethyl-3-methyl-2-nitroaniline. Two batches of this reaction sequence were carried out in parallel. NBS (23.4 g, 131 mmol) was added in one portion to a mixture of N-ethyl-3-methyl-2-nitroaniline (25.0 g, 138 mmol) in AcOH (125 mL) at 15° C. The mixture was stirred for 12 hours. The reaction mixtures from the two parallel batches were combined. The resulting mixture was concentrated under reduced pressure. DCM (500 mL) was added. The organic phase was washed with H₂O (300 mL×2), aqueous saturated NaHCO₃ solution (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (70.0 g, 97%) as a red solid which was used in the next step without further purification.

Step C: 4-Bromo-N¹-ethyl-3-methylbenzene-1,2-diamine. In one portion, Fe (32.3 g, 578 mmol) was added to a mixture of 4-bromo-N-ethyl-3-methyl-2-nitroaniline (50.0 g, 192 mmol) and NH₄Cl (62.1 g, 1.16 mol) in a mixture of ethanol (400 mL) and H₂O (100 mL) at 50° C. The resulting mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was then treated with H₂O (200 mL) and the aqueous layer was extracted with DCM (200 mL×3). These extractions resulted in several organic solvent fractions which were combined and washed with brine (100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (42.0 g, 94%) as a red solid which was used in the next step without further purification. ¹H NMR: (400 MHz, CDCl₃) δ 7.02 (d, J=8.4 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 3.45 (br s, 2H), 3.12 (d, J=6.6 Hz, 2H), 2.32 (br s, 3H), 1.31 (t, J=6.4 Hz, 3H).

Step D: 5-Bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole. To a mixture of 4-bromo-N¹-ethyl-3-methylbenzene-1,2-diamine (42.0 g, 183 mmol) in AcOH (200 mL) at 10° C. was added in one portion a solution of NaNO₂ (13.9 g, 201 mmol) in water (10.9 mL). The mixture was stirred at 15° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and added to H₂O (200 mL). This mixture was extracted with DCM (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 5:1, gradient elution) to afford the title compound (25.0 g, 40%) as a brown solid. MS (ESI): mass calcd. for C₉H₁₀BrN₃, 239.0; m/z found, 240.0 [M+H]⁺. ¹H NMR: (400 MHz, CDCl₃) δ 7.60 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 4.66 (q, J=7.6 Hz, 2H), 2.84 (s, 3H), 1.55-1.67 (m, 3H).

Intermediate 17: Ethyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

A mixture of 5-bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 16, 13.0 g, 54.1 mmol), ethyl prop-2-enoate (6.51 g, 64.9 mmol, 7.08 mL), Pd(PPh₃)₄ (5.0 g, 4.33 mmol), TEA (10.9 g, 108 mmol, 15.0 mL) in DMF (65 mL) was sparged with Na and then heated to 130° C. for 12 hours under Na. The residue was poured into water (200 mL) and stirred for 10 minutes. The aqueous layer was extracted with ethyl acetate (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (100 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 3:1, gradient elution) to afford the title compound (13.0 g, 92%) as a yellow solid. MS (ESI): mass calcd. for C₁₄H₁₇N₃O₂, 259.1; m/z found, 260.1 [M+H]⁺. ¹H NMR: (400 MHz, CDCl₃) δ 8.15 (d, J=15.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.42 (d, J=15.8 Hz, 1H), 4.63-4.74 (m, 2H), 4.31 (d, J=6.6 Hz, 2H), 2.93 (br s, 3H), 1.64 (t, J=6.6 Hz, 3H), 1.37 (t, J=6.2 Hz, 3H).

Intermediate 18: (5-Bromo-2-methylphenyl)methanol

Two batches of the reaction were carried out in parallel. LiAlH₄ (4.74 g, 124 mmol) was added to a solution of methyl 5-bromo-2-methylbenzoate (26.0 g, 113 mmol) in THF (260 mL) at 0° C. over a period of 10 minutes under N₂. The reaction mixture was warmed to 15° C. and stirred for 12 hours. The reaction mixture was quenched by sequential addition of the following: water (4.75 mL), 15% aqueous NaOH (4.75 mL), and water (14.2 mL). The aqueous phase was extracted with DCM (300 mL), and this organic solvent fraction was dried over anhydrous Na₂SO₄ and filtered. The filtrate from the two batches were combined and concentrated under reduced pressure to afford the title compound (42.0 g, 92%) as a white solid which was used in the next step without purification. ¹H NMR: (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.33 (dd, J=7.8, 1.6 Hz, 1H), 7.00-7.09 (m, 1H), 4.67 (s, 2H), 2.28 (s, 3H).

Intermediate 19: ((5-Bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane

TBSCl (89.96 g, 596.8 mmol) was added to a solution of 5-bromo-2-methylphenyl)methanol (80.0 g, 398 mmol) and imidazole (54.2 g, 796 mmol) in DMF (1.5 L) and the reaction mixture was stirred at 25° C. for 16 hour under Na. The reaction mixture was poured into H₂O (2 L) and extracted with EtOAc (1 L×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (2 L), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate) to afford the title compound (106 g, 83%) as a colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J=2.1 Hz, 1H), 7.16 (dd, J=8.0, 2.3 Hz, 1H), 6.87 (dd, J=8.1, 0.8 Hz, 1H), 4.53 (s, 2H), 2.08 (s, 3H), 0.84 (s, 9H).

Intermediate 20: 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate

Step A: 5-Bromo-2-methylbenzyl acetate. A solution of acetyl chloride (10.6 mL, 149 mmol) in DCM (30 mL) was added dropwise at 0° C. over a period of 30 minutes to a mixture of (5-bromo-2-methylphenyl)methanol (25.0 g, 124 mmol) and Et₃N (25.1 g, 248 mmol) in DCM (200 mL). After the addition, the reaction mixture was stirred at 15° C. for 3 hours. Water (200 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (200 mL×2). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 1:0 to 15:1, gradient elution) to afford the title compound (26.0 g, 86%) as a light yellow oil. ¹H NMR: (400 MHz, CDCl₃) δ 7.48 (d, J=0.8 Hz, 1H), 7.36 (dd, J=8.2, 1.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 5.08 (s, 2H), 2.29 (s, 3H), 2.13 (s, 3H).

Step B: 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate. B₂Pin₂ (32.6 g, 128 mmol), AcOK (15.7 g, 160 mmol) and Pd(dppf)Cl₂ (7.83 g, 10.7 mmol) were sequentially added to a solution of 5-bromo-2-methylbenzyl acetate (26.0 g, 106 mmol) in 1,4-dioxane (150 mL). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 15:1, gradient elution) to afford the title compound (5.0 g, 16%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.22 (d, J=7.4 Hz, 1H), 5.14 (s, 2H), 2.38 (s, 3H), 2.10 (s, 3H), 1.35 (s, 12H).

Intermediate 21: Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

Step A: Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. Five batches of this reaction sequence were carried out in parallel. [Rh(COD)Cl]₂ (1.33 g, 2.7 mmol) was added to a mixture of ethyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (Intermediate 17, 7.0 g, 27 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (Intermediate 20, 15.6 g, 54.0 mmol) and KOH (1.51 g, 27 mmol) in 1,4-dioxane (80 mL) and H₂O (8 mL). The mixture was stirred at 110° C. for 12 hours under Na. The five batches of reaction mixtures were combined, filtered and concentrated under reduced pressure and purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 2:1) to afford the title compound (30.0 g, 52%) as a yellow oil. ¹H NMR: (400 MHz, CDCl₃) δ 7.26-7.37 (m, 2H), 7.04-7.16 (m, 3H), 5.02 (s, 2H), 4.96 (t, J=7.5 Hz, 1H), 4.62 (q, J=7.6 Hz, 2H), 3.95-4.07 (m, 2H), 2.94-3.15 (m, 2H), 2.83 (br s, 3H), 2.22-2.31 (m, 3H), 2.03-2.09 (m, 3H), 1.58 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.0 Hz, 3H).

Step B: Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. A mixture of ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (1.39 g, 3.00 mmol) and potassium carbonate (870.4 mg, 6.298 mmol) in ethanol (15 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, then dissolved in water and DCM. The resulting biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered and concentrated to dryness under reduced pressure to provide the title compound (1.14 g, 96%) as a foam that was used without further purification. MS (ESI): mass calcd. for C₂₂H₂₇N₃O₃, 381.2; m/z found, 382.1 [M+H]⁺.

Intermediate 22: 1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde

Ozone was bubbled into a solution of ethyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (Intermediate 17, 13.0 g, 50.1 mmol) in DCM (130 mL) at −78° C. for 45 minutes. The reaction mixture was warmed to 15° C. and the ozone was purged from the reaction mixture by bubbling oxygen through the solution. Me₂S (30 mL) was added and the mixture was stirred at 15° C. for 12 hours. The reaction mixture was concentrated and purified by flash column chromatography (petroleum ether/ethyl acetate, 10:1 to 1:1, gradient elution) to afford the title compound (5.6 g, 58%) as a yellow solid. MS (ESI): mass calcd. for C₁₀H₁₁N₃O, 189.1; m/z found, 190.1 [M+H]⁺. ¹H NMR: (400 MHz, CDCl₃) δ 10.53 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 4.63-4.77 (m, 2H), 3.18 (s, 3H), 1.66 (t, J=6.6 Hz, 3H).

Intermediate 23: 4-Bromo-2-hydrazinyl-3-methylpyridine

A mixture of hydrazine hydrate (87.4 g, 1.75 mol) and 4-bromo-2-fluoro-3-methylpyridine (32.50 g, 171.0 mmol) was stirred at 25° C. for 6 days. Then aqueous NaOH solution (70 mL, 3 M) and water (70 mL) were added to the mixture and the suspension was stirred at 25° C. for 1 hour. The solid was filtered, washed with water (100 mL), and the solid was dried under reduced pressure to afford the title compound (28.9 g, 84%) as a white solid, which was used in the next step without further purification. ¹H NMR: (400 MHz, CD₃OD) δ 7.78 (d, J=5.6 Hz, 1H), 6.88 (d, J=5.6 Hz, 1H), 2.20 (s, 3H).

Intermediate 24: 7-Bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

TFAA (151.5 mL, 1.1 mol) was slowly added to 4-bromo-2-hydrazinyl-3-methylpyridine (Intermediate 23, 10.0 g, 49.5 mmol) and the mixture was heated to reflux for 24 hours under an atmosphere of N₂. The residue was dissolved in EtOAc (100 mL). The resulting solution washed with aqueous saturated NaHCO₃ solution (50 mL×2), brine (80 mL), dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound (13.0 g, 93.8%) as a yellow solid, which was used in the next step without further purification. ¹H NMR: (400 MHz, CDCl₃) δ 7.95 (d, J=7.2 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 2.79 (s, 3H).

Intermediate 25: Ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: Ethyl (E)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. A suspension of 7-bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24, 10.0 g, 35.7 mmol), ethyl acrylate (10.7 g, 107.1 mmol), Pd(PPh₃)₄ (3.3 g, 2.9 mmol) and TEA (10.8 g, 107.1 mmol) in DMF (100 mL) was sparged with N₂ for 10 minutes and then the mixture was heated to 110° C. and stirred under an atmosphere of N₂ for 58 hours. Water (100 mL) was added and the mixture was stirred at 25° C. for 10 minutes. The aqueous layer was extracted with CH₂Cl₂ (80 mL×2). These extractions resulted in several organic solvent fractions which were combined, washed with water (50 mL×4), brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 6:1) to afford the title compound (10.7 g, 84%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ 8.07 (d, J=7.2 Hz, 1H), 7.98 (d, J=16.0 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 6.50 (d, J=16.0 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 2.86 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).

Step B: Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Eight batches of the reaction were carried out in parallel. A mixture of ethyl (E)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (2.0 g, 6.7 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (Intermediate 20, 2.91 g, 10.0 mmol), [Rh(COD)Cl]₂ (329.5 mg, 0.668 mmol) and Na₂CO₃ (708.4 mg, 6.7 mmol) in 1,4-dioxane (18 mL) and water (3 mL), was sparged with N₂ for 10 minutes and stirred at 80° C. under an atmosphere of N₂ for 25 hours. The eight batches of the reaction were combined. The resulting mixture was filtered to remove solids and the filtrate was collected. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 15:1 to 8:1, gradient elution) to afford the title compound (18.0 g, 75%) as a yellow gum. ¹H NMR: (400 MHz, CDCl₃) δ 8.01 (d, J=7.2 Hz, 1H), 7.18-7.07 (m, 3H), 6.95 (d, J=7.2 Hz, 1H), 5.07 (s, 2H), 4.97 (t, J=8.0 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.14 (dd, J=15.6, 6.8 Hz, 1H), 3.01 (dd, J=15.6, 6.8 Hz, 1H), 2.86 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.17 (t, J=7.2 Hz, 3H).

Step C: Ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Two batches of the reaction were carried out in parallel. Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (8.5 g, 18.3 mmol) was dissolved in ethanol (200 mL) and stirred at 25° C. 2 M Aqueous HCl (90 mL) was added to the above solution and the mixture was stirred at 25° C. for 24 hours. The two batches of the reaction were combined and the resulting reaction mixture was slowly quenched with aqueous saturated NaHCO₃ solution. Ethanol was removed under reduced pressure and the aqueous layer was extracted with CH₂Cl₂ (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 8:1 to 4:1, gradient elution) to afford the title compound (10.0 g, 65%) as a yellow gum. MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.2 [M+H]⁺. ¹H NMR: (400 MHz, CDCl₃) δ 7.99 (d, J=7.2 Hz, 1H), 7.25 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 4.96 (t, J=8.0 Hz, 1H), 4.67 (s, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.15 (dd, J=15.6, 6.8 Hz, 1H), 3.01 (dd, J=15.6, 6.8 Hz, 1H), 2.85 (s, 3H), 2.29 (s, 3H), 1.16 (t, J=7.2 Hz, 3H).

Intermediate 26: Ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The mixture of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate enantiomers (Intermediate 25, 16 g) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 65% CO₂, 35% MeOH) to afford two enantiomers. The first eluting isomer (8.04 g) was designated (*S). MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=7.2 Hz, 1H), 7.27-7.26 (m, 1H), 7.14-7.10 (m, 1H), 7.07-7.03 (m, 1H), 6.93 (d, J=7.3 Hz, 1H), 5.01-4.91 (m, 1H), 4.67 (d, J=3.2 Hz, 2H), 4.11-4.02 (m, 2H), 3.20-3.11 (m, 1H), 3.08-2.98 (m, 1H), 2.84 (s, 3H), 2.28 (s, 3H), 2.15-2.06 (m, 1H), 1.20-1.13 (m, 3H).

Intermediate 27: Ethyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The second eluting isomer (7.94 g) from the separation of isomers by chiral SFC described in Intermediate 26 was designated (*R). MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=7.2 Hz, 1H), 7.29-7.24 (m, 1H), 7.14-7.10 (m, 1H), 7.08-7.03 (m, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.99-4.94 (m, 1H), 4.67 (d, J=5.0 Hz, 2H), 4.12-4.01 (m, 2H), 3.20-3.11 (m, 1H), 3.08-2.97 (m, 1H), 2.84 (s, 3H), 2.28 (s, 3H), 2.15-2.09 (m, 1H), 1.16 (t, J=7.1 Hz, 3H).

Intermediate 28: 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde

Step A: 8-Methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine. A mixture of 7-bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24, 38.0 g, 136 mmol), potassium trifluoro(vinyl)borate (36.3 g, 271 mmol), K₃PO₄ (86.0 g, 405 mmol), 1,4-dioxane (400 mL), and H₂O (80 mL) was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl₂ (5.0 g, 6.8 mmol). The resulting mixture was sparged with Ar for another 5 minutes and then stirred at 110° C. for 16 hours. After cooling to room temperature, the resulting suspension was filtered. The filtrate was poured into H₂O (100 mL) and the aqueous layer was extracted with ethyl acetate (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:1, gradient elution) to afford the title compound (33 g, 99%) as a brown solid. MS (ESI): mass calcd. for C₁₀H₈F₃N₃ 227.1 m/z, found 227.9 [M+H]⁺.

Step B: 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. K₂OsO₄.2H₂O (1.6 g, 4.3 mmol) was added to a solution of 8-methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (25.0 g, 110 mmol) and 1,4-dioxane (600 mL) in distilled H₂O (600 mL). The resulting mixture was treated with NaIO₄ (75.0 g, 351 mmol), stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure. The residue was diluted with H₂O (100 mL) and the aqueous layer was extracted with ethyl acetate (150 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:1, gradient elution) to afford the title compound (22 g, 87%) as a gray solid. MS (ESI): mass calcd. for C₉H₆F₃N₃O, 229.1 m/z; found 230.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.52 (d, J=6.4 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 2.98 (s, 3H).

Intermediate 29: 5-Bromo-1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole

Step A: N-Cyclopropyl-3-methyl-2-nitroaniline. Three batches of the reaction were carried out in parallel. A mixture of 1-fluoro-3-methyl-2-nitrobenzene (10 g, 64.46 mmol), cyclopropanamine (18.40 g, 322.3 mmol, 22.33 mL) and TEA (13.05 g, 128.9 mmol) in MeCN (30 mL) was stirred at 112° C. for 16 hours. After cooling to room temperature, the reaction mixtures from the three batches were combined, diluted with EtOAc (200 mL) and sequentially washed with 10% aqueous NaHCO₃ solution (100 mL) and brine (100 mL). The organic layer was concentrated under reduced pressure to afford the title compound (35 g, 94%) as a yellow solid, which was used without further purification.

Step B: 4-Bromo-N-cyclopropyl-3-methyl-2-nitroaniline. NBS (30.79 g, 172.9 mmol) was added to a mixture of N-cyclopropyl-3-methyl-2-nitroaniline (35.0 g, 182 mmol) in AcOH (300 mL) at 20° C., and the reaction was stirred at 20° C. for 6 hours. The reaction was poured into water (1000 mL) and the aqueous layer was extracted with EtOAc (500 mL×2). These extractions resulted in several organic solvent fractions which were combined, washed with aqueous saturated NaHCO₃(500 mL×3) solution, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (46 g, 93%) as a red solid. MS (ESI): mass calcd. for C₁₀H₁₁BrN₂O₂, 270.0; m/z found, 270.9 [M+H]⁺.

Step C: 4-Bromo-N¹-cyclopropyl-3-methylbenzene-1,2-diamine. A mixture of Raney Ni (8.60 g, 100 mmol) and 4-bromo-N-cyclopropyl-3-methyl-2-nitroaniline (30.0 g, 110 mmol) in ethanol (300 mL) was stirred at room temperature under H₂ (50 psi) for 6 hours. The reaction mixture was filtered, washed with ethanol (50 mL×2) and the solvents were removed under reduced pressure to afford the title compound (21 g, 61%) as a red solid. MS (ESI): mass calcd. for C₁₀H₁₃BrN₂, 240.0; m/z found, 240.7 [M+H]⁺.

Step D: 5-Bromo-1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole. A solution of NaNO₂ (7.76 g, 112 mmol) in H₂O (30 mL) was added to a solution of 4-bromo-N¹⁻-cyclopropyl-3-methylbenzene-1,2-diamine (26.0 g, 107 mmol) in 2 M HCl (250 mL, 500 mmol) at 0° C. and the reaction was stirred at 0-10° C. for 1 hour. CH₂Cl₂ (300 mL) was added to the reaction mixture, and the aqueous phase was extracted with CH₂Cl₂ (200 mL×2). These extractions resulted in several organic solvent fractions which were combined, washed with brine (200 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/CH₂Cl₂, 10:1 to 3:1, gradient elution) to afford the title compound (8.4 g, 27%) as an off white solid. MS (ESI): mass calcd. for C₁₀H₁₀BrN₃, 251.0; m/z found, 251.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.61 (d, J=8.7 Hz, 1H), 7.38-7.35 (m, 1H), 3.80-3.69 (m, 1H), 2.82 (s, 3H), 1.38-1.27 (m, 4H).

Intermediate 30: 8-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

A mixture of 7-bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24, 1.2 g, 4.3 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.4 g, 21 mmol), KOAc (1.26 g, 12.8 mmol) and toluene (15 mL) was sparged with N₂ for 5 minutes and then treated with Pd(dppf)Cl₂ (314 mg, 0.429 mmol). The mixture was sparged with N₂ for another 5 minutes and then stirred at 80° C. for 36 hours. After cooling to room temperature, the suspension was filtered through diatamaceous earth such as Celite® and washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 50:1 to 5:1, gradient elution) to afford the title compound (1.1 g, 63%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=6.8 Hz, 1H), 7.30 (d, J=7.1 Hz, 1H), 2.95 (s, 3H), 1.36 (s, 12H).

Intermediate 31: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Thionyl chloride (0.85 mL, 12 mmol) was added to a solution of ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Intermediate 21, 2.94 g, 7.71 mmol) in DCM (38 mL). Five drops of DMF were added to the solution, and the reaction was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (3.05 g, 99%) as an oil which was used without further purification. MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂, 399.2; m/z found, 400.0 [M+H]⁺.

Intermediate 32: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Step A: Ethyl (E)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. 1,4-Dioxane (17 mL) and water (5 mL) were added to a mixture of 5-bromo-1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 29, 1.25 g, 4.96 mmol), potassium carbonate (1.38 g, 9.99 mmol), Pd(dppf)Cl₂ (364 mg, 0.497 mmol), and ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.37 g, 6.05 mmol). The mixture was heated to 90° C. and stirred for 4.5 hours. After this time, the reaction was cooled to room temperature, then filtered through a pad of diatomaceous earth such as Celite®. The pad was rinsed with ethyl acetate. The filtrate was collected, washed with brine, then dried over MgSO₄, filtered and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0 to 20% ethyl acetate/DCM, gradient elution) to afford the title compound (980 mg, 73%). MS (ESI): mass calcd. for C₁₅H₁₇N₃O₂, 271.1; m/z found, 272.2 [M+H]⁺.

Step B: Ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. (3-(Hydroxymethyl)-4-methylphenyl)boronic acid (907 mg, 5.46 mmol), triethylamine (0.76 mL, 5.5 mmol), and [Rh(COD)Cl]₂ (92 mg, 0.19 mmol) were added to a solution of ethyl (E)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (980 mg, 3.6 mmol) in 1,4-dioxane (25 mL) and water (12 mL). The mixture was stirred at 95° C. for 2 hours. Additional (3-(hydroxymethyl)-4-methylphenyl)boronic acid (905 mg, 5.45 mmol) and [Rh(COD)Cl]₂ (92 mg, 0.19 mmol) were then added and the reaction was stirred at 95° C. for 1 hour. After this time, the reaction was cooled to room temperature, then diluted with water and ethyl acetate. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0 to 50% ethyl acetate/hexanes, gradient elution) to afford the title compound (1.2 g, 84%). MS (ESI): mass calcd. for C₂₃H₂₇N₃O₃, 393.2; m/z found, 394.1 [M+H]⁺.

Step C: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. The title compound (1.2 g, 97%) was prepared using analogous conditions as described in Intermediate 31 where ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate was used instead of ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₂, 411.2; m/z found, 412.1 [M+H]⁺.

Intermediate 33: 5-Bromo-7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazole

Step A: 2-(Difluoromethoxy)-6-nitroaniline. To a solution of 2-amino-3-nitrophenol (20.2 g, 131 mmol) in DMF (130 mL) and water (13 mL) was added sodium chlorodifluoroacetate (49.8 g, 327 mmol) and K₂CO₃ (27.1 g, 196 mmol). The reaction mixture was heated under Ar to 100° C. under a reflux condenser for 2.5 hours. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL). The organic phase was washed with 1 N aqueous NaOH (200 mL). The basic aqueous phase was extracted with EtOAc (200 mL). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 40% DCM/heptane), to afford the title compound (14.6 g, 55%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (dd, J=8.8, 1.3 Hz, 1H), 7.30-7.25 (m, 1H), 6.67 (dd, J=8.8, 7.8 Hz, 1H), 6.54 (t, J=72.8 Hz, 1H), 6.47-6.25 (m, 2H).

Step B: 4-Bromo-2-(difluoromethoxy)-6-nitroaniline. To a solution of 2-(difluoromethoxy)-6-nitroaniline (14.6 g, 71.3 mmol) in AcOH (182 mL) was added sodium acetate (9.36 g, 114 mmol) followed by bromine (4.05 mL, 78.5 mmol). The reaction mixture was stirred at room temperature under air for 20 minutes. Water (180 mL) was added and the precipitate was collected by vacuum filtration and air-dried. This yellow solid was further dried under vacuum, to afford the title compound (15.3 g, 76%). MS (ESI): mass calcd. for C₇H₅BrF₂N₂O₃, 284.0; m/z found, 284.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 6.56 (t, J=72.0 Hz, 1H), 6.49-6.26 (m, 2H).

Step C: 4-Bromo-2-(difluoromethoxy)-N-methyl-6-nitroaniline. To a solution of 4-bromo-2-(difluoromethoxy)-6-nitroaniline (15.3 g, 54.2 mmol) in DMF (100 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 2.60 g, 65.0 mmol) and the reaction mixture was stirred at 0° C. under Ar for 45 minutes. Iodomethane (3.71 mL, 59.6 mmol) was then added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was poured into water (250 mL). The mixture was filtered and the precipitate was washed with water, air-dried, and dried under vacuum to yield the title compound (15.7 g) which was used without further purification in the next reaction. MS (ESI): mass calcd. for C₈H₇BrF₂N₂O₃, 298.0; m/z found, 299.0 [M+H]⁺.

Step D: 4-Bromo-6-(difluoromethoxy)-N¹-methylbenzene-1,2-diamine. To a solution of 4-bromo-2-(difluoromethoxy)-N-methyl-6-nitroaniline (15.7 g, 52.9 mmol) in AcOH (160 mL) was added zinc (10.4 g, 159 mmol). The reaction mixture was stirred for 16 hours under Ar at room temperature. The reaction mixture was filtered through a bed of diatomaceous earth such as Celite®, washing thoroughly with EtOAc. The filtrate was concentrated to provide a residue. The residue was concentrated twice from toluene under reduced pressure to remove residual AcOH. The residue was purified by flash column chromatography (eluent: 0 to 40% EtOAc/heptanes, gradient elution), to afford the title compound (6.34 g, 45%) as a red oil. MS (ESI): mass calcd. for C₈H₉BrF₂N₂O, 268.0; m/z found, 269.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.72 (d, J=2.0 Hz, 1H), 6.65-6.63 (m, 1H), 6.47 (t, J=73.8 Hz, 1H), 3.88-4.16 (m, 2H), 2.66 (s, 3H).

Step E: 5-Bromo-7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazole. To 4-bromo-6-(difluoromethoxy)-M-methylbenzene-1,2-diamine (6.34 g, 23.7 mmol) was added H₂SO₄ (10% aqueous solution, 24 mL, 450 mmol). The resulting suspension was cooled to 0° C. Sodium nitrite (2.29 g, 33.2 mmol) was added slowly over 6 minutes, and the reaction mixture was stirred at 0° C. for 30 minutes. Water (50 mL) was added and the mixture was filtered. The collected tan solid was washed with water (twice) and air-dried. It was subsequently dried further under vacuum to provide the title compound (6.71 g) which was used without further purification in the next step. MS (ESI): mass calcd. for C₈H₆BrF₂N₃O, 279.0; m/z found, 280.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=1.0 Hz, 1H), 7.28-7.27 (m, 1H), 6.72 (t, J=72.0 Hz, 1H), 4.45 (s, 3H).

Intermediate 34: 5-Bromo-7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazole

Step A: 2-Cyclopropoxy-6-nitroaniline. A mixture of cesium hydroxide monohydrate (16.08 g, 95.76 mmol), DMSO (50 mL), 2-amino-3-nitrophenol (14.71 g, 95.44 mmol), and cyclopropyl bromide (21.1 g, 174 mmol) was placed in a 500 mL high pressure flask with a screw cap, flushed with argon for 1 minute, then sealed and stirred at 150° C. After 16 hours, the reaction was cooled to room temperature, treated with additional cyclopropyl bromide (24.44 g, 202.0 mmol), argon was bubbled through the solution for 30 seconds, then the reaction vessel was re-sealed and stirred at 150° C. After 24 hours, the reaction was cooled to room temperature and the reaction mixture was allowed to sit for 9 weeks. The reaction mixture was then poured into water (400 mL) and 5:1 diethyl ether:DCM (600 mL) was added. A dark emulsion formed and it was filtered through diatomaceous earth such as Celite® to allow the organic and aqueous layers to separate. The aqueous layer of the filtrate was separated and was extracted with DCM (1×600 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was initially purified by flash column chromatography (eluent: heptanes/ethyl acetate, 95:5 to 70:30, gradient elution). Since impurities were still present, the residue was subsequently purified again by flash column chromatography (eluent: heptanes/ethyl acetate, 95:5 to 80:20, gradient elution) to provide the title compound (2.22 g, 12%). MS (ESI): mass calcd. for C₉H₁₀N₂O₃, 194.1; m/z found, 195.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, J=1.3, 8.8 Hz, 1H), 7.28-7.24 (m, 1H), 6.62 (t, J=8.2 Hz, 1H), 6.33 (br s, 2H), 3.83-3.78 (m, 1H), 0.90-0.80 (m, 4H).

Step B: 4-Bromo-2-cyclopropoxy-6-nitroaniline. A mixture of 4-bromo-2-cyclopropoxy-6-nitroaniline (2.10 g, 10.8 mmol), HOAc (23 mL), and sodium acetate (1.405 g, 17.13 mmol) was stirred at 10-15° C. while a solution of bromine (1.92 g, 12.0 mmol) in HOAc (5 mL) was added dropwise over 6 minutes. The cooling bath was immediately removed and the reaction stirred at room temperature. After 2.5 hours, the reaction was treated with water (90 mL) over 3-4 minutes, filtered, and the filter cake washed with water (2×25 mL) and dried under reduced pressure to provide the title compound (2.92 g, 99%). MS (ESI): mass calcd. for C₉H₉BrN₂O₃, 272.0; m/z found, 273.0, 275.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 6.36 (br s, 2H), 3.80 (tt, J=5.8, 3.0 Hz, 1H), 0.95-0.82 (m, 5H).

Step C: 4-Bromo-2-cyclopropoxy-N-methyl-6-nitroaniline. A solution of 4-bromo-2-cyclopropoxy-6-nitroaniline (2.79 g, 10.2 mmol) and DMF (41 mL) was stirred at 0° C. under argon while NaH (60.8% dispersion in mineral oil, 0.451 g, 11.4 mmol) was added in one portion. The reaction was stirred for 30 minutes. While keeping the reaction mixture at 0° C., a solution of MeI (1.605 g, 11.31 mmol) in DMF (8.5 mL, 10.2 mmol) was added dropwise over 10 minutes. The reaction was stirred at 0° C. for an additional 40 minutes, and was then treated with water (60 mL) dropwise over 6 minutes. Stirring was stopped while still at 0° C. for ˜30 minutes and the reaction mixture was then filtered. The filter cake was washed with water (2×25 mL), dried under reduced pressure, and purified by flash column chromatography (eluent: heptanes/ethyl acetate, 100:0 to 80:20, gradient elution) to provide the title compound (1.54 g, 53%). MS (ESI): mass calcd. for C₁₀H₁₁BrN₂O₃, 286.0; m/z found, 287.1, 289.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=2.0 Hz, 1H), 7.65 (br s, 1H), 7.32 (d, J=2.5 Hz, 1H), 3.72 (tt, J=5.9, 3.0 Hz, 1H), 3.13 (d, J=5.1 Hz, 3H), 0.90-0.80 (m, 4H).

Step D: 4-Bromo-6-cyclopropoxy-M-methylbenzene-1,2-diamine. A solution of 4-bromo-2-cyclopropoxy-N-methyl-6-nitroaniline (1.51 g, 5.26 mmol) and HOAc (26 mL) was stirred at room temperature while iron powder (1.47 g, 26.3 mmol) was added in one portion. The reaction was stirred for 2 hours and then diluted with EtOAc (30 mL) and filtered through diatomaceous earth such as Celite®. The filter cake was washed with EtOAc (4×30 mL), the combined filtrates were concentrated to dryness under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and 10 M NaOH (20 mL). The resulting emulsion was filtered through diatomaceous earth such as Celite® and the filter cake washed with EtOAc (2×50 mL). The aqueous layer was extracted with EtOAc (1×100 mL) and the organic solvent fractions were combined, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C₁₀H₁₀BrN₂O, 256.0; m/z found, 257.0, 259.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.78 (d, J=2.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 3.94-3.82 (m, 2H), 3.82-3.58 (m, 1H), 2.65-2.57 (m, 3H), 0.84-0.70 (m, 4H).

Step E: 5-Bromo-7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazole. A thick slurry of 4-bromo-6-cyclopropoxy-M-methylbenzene-1,2-diamine (1.39 g, 5.41 mmol) in water (4.9 mL) and H₂SO₄ (1.2 mL, 23 mmol) at 0° C. was treated with a solution of sodium nitrite (0.536 g, 7.77 mmol) in water (4.9 mL) as an intermittent thin stream by syringe over 4 minutes with periodic spatula stirring of the thick mixture. The mixture was intermittently stirred with a spatula and shaken at 0° C. for an additional 10 minutes, at which point the reaction thinned to an easily stirring mixture. After 35 minutes at 0° C., the reaction was quenched with water (10 mL), allowed to chill in the ice bath, and filtered. The filter cake was washed with water (4×10 mL) and the filter cake was dried under reduced pressure to provide the title compound (1.31 g, 90%) which was used without further purification. MS (ESI): mass calcd. for C₁₀H₁₀BrN₃O, 267.0; m/z found, 268.0, 270.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=1.5 Hz, 1H), 7.21 (d, J=1.0 Hz, 1H), 4.39 (s, 3H), 3.94-3.88 (m, 1H), 0.98-0.85 (m, 4H).

Intermediate 35: Ethyl (E)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate

Step A: N-(Cyclopropylmethyl)-3-methyl-2-nitroaniline. A solution of 3-fluoro-2-nitrotoluene (6.92 g, 44.6 mmol), cyclopropylmethylamine (4.45 g, 62.6 mmol) and TEA (6.2 mL, 45 mmol) was heated in a sealed tube to 150° C. under argon. After 4 hours, the reaction was cooled to room temperature, combined, and partitioned between EtOAc (80 mL) and 1 M NaH₂PO₄ (80 mL). The organic solvent fraction was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound contaminated with 7 mol % EtOAc (9.36 g, 102%). MS (ESI): mass calcd. for C₁₁H₁₄N₂O₂, 206.2; m/z found, 207.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21 (t, J=7.8 Hz, 1H), 6.62 (d, J=8.6 Hz, 2H), 6.51 (d, J=7.6 Hz, 1H), 3.04 (dd, J=7.1, 5.1 Hz, 2H), 2.47 (s, 3H), 1.18-1.08 (m, 1H), 0.66-0.55 (m, 2H), 0.33-0.24 (m, 2H).

Step B: 4-Bromo-N-(cyclopropylmethyl)-3-methyl-2-nitroaniline. A mixture of N-(cyclopropylmethyl)-3-methyl-2-nitroaniline (9.2 g, 44.6 mmol), HOAc (90 mL), and N-bromosuccinimide (7.93 g, 44.6 mmol) was stirred at 0° C. for 4 minutes and then was warmed to room temperature. After 3 hours, the reaction was concentrated under reduced pressure to give 35 g of a clear orange-red oil. 10 M NaOH (40 mL) was added in portions to the clear orange-red oil, and then the reaction mixture was partitioned between water (60 mL) and EtOAc (100 mL). The aqueous layer (pH ˜14) was extracted with EtOAc (1×50 mL), and the organic solvent fractions were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (12.1 g, 95%). MS (ESI): mass calcd. for C₁₁H₁₃BrN₂O₂, 284.0; m/z found, 285.0, 287.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=9.1 Hz, 1H), 6.52 (d, J=9.1 Hz, 1H), 5.78 (br s, 1H), 2.99 (dd, J=7.1, 5.1 Hz, 2H), 2.44 (s, 3H), 1.14-1.04 (m, 1H), 0.63-0.54 (m, 2H), 0.29-0.22 (m, 2H).

Step C: 4-Bromo-N¹-(cyclopropylmethyl)-3-methylbenzene-1,2-diamine. A mixture of 4-bromo-N-(cyclopropylmethyl)-3-methyl-2-nitroaniline (11.71 g, 41.07 mmol), HOAc (123 mL), and iron powder (11.48 g, 205.6 mmol) was stirred at room temperature for 2.5 hours. The reaction was then filtered through diatomaceous earth such as Celite®, and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated under reduced pressure to provide 33.7 g of a dark oil. Then, 3 M NaOH (133 mL) and EtOAc (1×100 mL) was added to the residue, the resulting emulsion was filtered through diatomaceous earth such as Celite® and the filter cake washed with EtOAc (2×50 mL). This resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure to provide the title compound (9.6 g, 91%). MS (ESI): mass calcd. for C₁₁H₁₅BrN₂, 255.2; m/z found, 255.1, 257.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.99 (d, J=8.6 Hz, 1H), 6.41 (d, J=8.6 Hz, 1H), 3.51 (br s, 3H), 2.90 (d, J=6.6 Hz, 2H), 2.31 (s, 3H), 1.21-1.07 (m, 1H), 0.63-0.50 (m, 2H), 0.29-0.14 (m, 2H).

Step D: 5-Bromo-1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole. A solution containing 4-bromo-N¹-(cyclopropylmethyl)-3-methylbenzene-1,2-diamine (9.34 g, 36.6 mmol), HOAc (110 mL), and MeOH (110 mL) was stirred at 0° C. while a solution of sodium nitrite (3.55 g, 51.4 mmol) in water (50 mL) was added dropwise over 5 minutes via pressure-equalizing addition funnel. The reaction was stirred at room temperature for 2 hours, and then partially concentrated under reduced pressure to remove the volatile organic solvents. The remaining solution was poured onto ice (300 mL), neutralized with solid K₂CO₃ to pH ˜7, and extracted with EtOAc (2×100 mL). These extractions resulted in multiple organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography using two different sets of conditions. The first column used heptanes/ethyl acetate, 80:20 to 60:40, gradient elution as the eluent and the second column used heptanes/ethyl acetate 90:10 to 75:25, gradient elution as the eluent to provide the title compound (3.9 g, 40%). MS (ESI): mass calcd. for C₁₁H₁₂BrN₃, 265.0; m/z found, 266.0, 268.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=8.6 Hz, 1H), 7.28 (d, J=9.6 Hz, 1H), 4.49 (d, J=7.1 Hz, 2H), 2.84 (s, 3H), 1.43-1.33 (m, 1H), 0.70-0.59 (m, 2H), 0.54-0.46 (m, 2H).

Step E: Ethyl (E)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. A mixture of 5-bromo-1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole (3.9 g, 14.7 mmol), DMF (7.3 mL), DIPEA (7.6 mL, 44 mmol), tri-o-tolylphosphine (0.894 g, 2.94 mmol), ethyl acrylate (3.2 mL, 29 mmol), and Pd(OAc)₂ (0.331 g, 1.47 mmol) was stirred under argon at 80° C. After 60 hours, the reaction was cooled to room temperature, partitioned between 0.5 M NaH₂PO₄ (100 mL) and 1:1 EtOAc:diethyl ether (100 mL). The organic solvent fraction was separated and washed with 0.5 M NaH₂PO₄ (1×100 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: heptanes/ethyl acetate, 60:40 to 80:20, gradient elution) to provide 2.9 g of the title compound which still contained some impurities. To further purify the title compound it was heated to reflux in 200 mL diethyl ether for ˜10 minutes, cooled to room temperature, and filtered. The filtrate was concentrated to dryness under reduced pressure to provide the title compound (2.49 g, 60%). MS (ESI): mass calcd. for C₁₆H₁₉N₃O₂, 285.2; m/z found, 286.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=15.7 Hz, 1H), 7.71 (d, J=9.1 Hz, 1H), 7.39 (d, J=9.1 Hz, 1H), 6.42 (d, J=15.7 Hz, 1H), 4.50 (d, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 2.93 (s, 3H), 1.44-1.34 (m, 4H), 0.69-0.62 (m, 2H), 0.52-0.47 (m, 2H).

Intermediate 36: 2,2′,3,3′,5,6-Hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2-Chloropyridine-3-sulfonyl chloride (4.24 g, 20.0 mmol) was added to a mixture of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (2.62 g, 20.0 mmol) and K₂CO₃ (4.14 g, 30.0 mmol) in THF (70 mL) and water (15 mL) at room temperature. After 2 hours, H₂O (30 mL) was added and the aqueous layer was extracted with EtOAc (60 mL×2). These extractions resulted in several organic solvent fractions which were combined and concentrated under reduced pressure to provide 2-chloro-N-((1-hydroxycyclohexyl)methyl)pyridine-3-sulfonamide. MS (ESI): mass calcd. for C₁₁H₁₇ClN₂O₃S, 304.1; m/z found, 307.1 [M+H]⁺.

Step B: 2-Chloro-N-((1-hydroxycyclohexyl)methyl)pyridine-3-sulfonamide was re-dissolved in DMF (20 mL), and K^(t)OBu (5.60 g, 50 mmol) was added and the mixture was heated at 110° C. for 2 hours. The mixture was cooled to room temperature and pH was adjusted to ˜3-4 by adding 1 M aqueous HCl solution. The precipitated solid was filtered and dried under reduced pressure to afford the title compound (3.20 g, 59%). MS (ESI): mass calcd. for C₁₁H₁₄N₂O₄S, 270.1; m/z found, 271.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.56-8.37 (m, 1H), 8.25 (dd, J=7.7, 1.9 Hz, 1H), 7.49-7.29 (m, 1H), 4.01 (s, 2H), 3.75-3.52 (m, 4H), 1.84-1.57 (m, 4H).

Intermediate 37: 8′-Methyl-2,2′,3,3′,5,6-Hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2-Chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methylpyridine-3-sulfonamide. 2-Chloro-5-methylpyridine-3-sulfonyl chloride (2.60 g, 20 mmol) was added to a mixture of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (2.62 g, 20.0 mmol) and K₂CO₃ (4.14 g, 30.0 mmol) in THF (70 mL) and water (15 mL) at room temperature. After 2 hours, H₂O (30 mL) and ethyl acetate were added. The layers were separated and the aqueous layer was further extracted with ethyl acetate (60 mL×2). These extractions resulted in several organic solvent fractions which were combined and concentrated to provide the title compound (4.30 g, 68%). MS (ESI): mass calcd. for C₁₂H₁₇ClN₂O₄S, 320.1; m/z found, 321.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.51-8.36 (m, 1H), 8.34-8.24 (m, 1H), 3.81-3.57 (m, 4H), 2.99 (s, 2H), 2.45 (s, 3H), 1.76-1.60 (m, 2H), 1.54-1.37 (m, 2H).

Step B: 8′-Methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. 2-Chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methylpyridine-3-sulfonamide (4.20 g, 13.2 mmol) was dissolved into DMSO (12 mL), and K^(t)OBu (3.68 g, 32.8 mmol) was added. The mixture was heated to 95° C. for 2 hours. The mixture was then cooled, the pH of the mixture was adjusted to 5 by adding 5 M aqueous HCl solution. Ethyl acetate was added to the solution. The aqueous layer was separated and extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% EtOAc/hexanes) to provide the title compound (1.70 g, 45%). MS (ESI): mass calcd. for C₁₂H₁₆N₂O₄S, 284.1; m/z found, 285.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.29 (d, J=2.2 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 4.14-3.90 (m, 2H), 3.79-3.63 (m, 2H), 3.54 (s, 2H), 2.41 (s, 3H), 1.67 (d, J=6.0 Hz, 4H).

Intermediate 38: 7-Bromo-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine

2,2-Difluoroacetic anhydride (34.50 g, 197.9 mmol) was added slowly to 4-bromo-2-hydrazinyl-3-methylpyridine (Intermediate 23, 2.00 g, 9.99 mmol). The reaction initially started to reflux and the solids turned yellow, but within 5 minutes the reaction was homogeneous. The reaction mixture was warmed to 50° C. After 18 hours, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added, followed by saturated aqueous NaHCO₃ until the pH of the solution was 7-8 and the layers were separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organics were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% EtOAc/hexanes, gradient elution) to afford the title compound (2.50 g, 96%) as a white solid. MS (ESI): mass calcd. for C₈H₆BrF₂N₃, 262.1; m/z found, 262.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=7.2 Hz, 1H), 7.18-7.09 (m, 2H), 2.76 (d, J=0.8 Hz, 3H).

Intermediate 39: (*S)-7a-Methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

The mixture of 7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide enantiomers (Intermediate 8, 2.9 g) was separated by chiral SFC (stationary phase: Whelk O1 (S,S) 5 μm 250×21.1 mm, Mobile phase: 65% CO₂, 35% isopropanol) to afford two enantiomers. The first eluting isomer (1.3 g) was designated (*S). MS (ESI): mass calcd. for C₁₁H₁₅N₃O₂S, 253.1; m/z found, 254.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.40-8.36 (m, 1H), 8.13-8.10 (m, 1H), 6.93-6.88 (m, 1H), 4.85-4.72 (m, 1H), 4.06-3.97 (m, 1H), 3.67-3.56 (m, 2H), 3.18-3.11 (m, 1H), 2.07-1.88 (m, 4H), 0.94 (s, 3H).

Intermediate 40: (*R)-7a-Methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (1.25 g) from the separation of isomers by chiral SFC described in Intermediate 39 was designated (*R). MS (ESI): mass calcd. for C₁₁H₁₅N₃O₂S, 253.1; m/z found, 254.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.41-8.36 (m, 1H), 8.14-8.09 (m, 1H), 6.92-6.89 (m, 1H), 4.90-4.74 (m, 1H), 4.07-3.94 (m, 1H), 3.69-3.56 (m, 2H), 3.19-3.09 (m, 1H), 2.07-1.88 (m, 4H), 0.94 (s, 3H).

Intermediate 41: 5-bromo-2-methylbenzyl pivalate

Pivaloyl chloride (119 mL, 966 mmol) was added dropwise to a solution of (5-bromo-2-methylphenyl)methanol (87.8 g, 437 mmol), triethylamine (243 mL, 1.75 mol), and dichloromethane (800 mL) that had been cooled to 0° C. The resulting mixture was allowed to slowly warm to room temperature and stirred for 4 hours before pouring it into water (600 mL). The aqueous layer was extracted with dichloromethane (300 mL×2). These extractions resulted in several organic solvent fractions which were combined, washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether) to afford the title compound (160 g, 96%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (d, J=2.2 Hz, 1H), 7.39 (dd, J=8.1, 2.2 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 5.03 (s, 2H), 2.21 (s, 3H), 1.13 (s, 9H).

Intermediate 42: 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl pivalate

A mixture of 5-bromo-2-methylbenzyl pivalate (Intermediate 41, 40.0 g, 140 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (53.5 g, 211 mmol), KOAc (55.1 g, 561 mmol), and 1,4-dioxane (600 mL) was sparged with N₂ for 5 minutes and then treated with Pd(dppf)Cl₂ (8.2 g, 11 mmol). The mixture was sparged with N₂ for another 5 minutes and then heated to 90° C. for 4 hours before cooling to room-temperature. This mixture was then poured into H₂O (200 mL), and extracted with ethyl acetate (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. This residue was initially purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1) and further purified by preparative HPLC using a SANPONT C₁₈, 250 mm×50 mm×5 μm column (eluent: 50% to 95% (v/v) CH₃CN and H₂O with 0.1% TFA) to afford the titiled compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 5.09 (s, 2H), 2.31 (s, 3H), 1.28 (s, 12H), 1.14 (s, 9H).

Intermediate 43: Tert-butyldimethyl((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane

1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (655 mg, 0.79 mmol) was added to a mixture of ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 5.00 g, 15.9 mmol), bis(pinacolato)diboron (8.19 g, 32.3 mmol), potassium acetate (4.64 g, 47.3 mmol) and 1,4-dioxane (45.0 mL). The reaction mixture was stirred at 90° C. under nitrogen for 4 hours. After filtration of the mixture through a pad of diatomaceous earth, the filtrate was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water and the aqueous layer was further extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0 to 50% ethyl acetate/hexanes, gradient elution) to afford the title compound (4.00 g, 70%). ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J=1.3 Hz, 1H), 7.55-7.51 (m, 1H), 7.06 (d, J=7.4 Hz, 1H), 4.61 (s, 2H), 2.25 (s, 3H), 1.24 (s, 12H), 0.84 (s, 9H), 0.10 (s, 6H).

Intermediate 45: 3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde

Step A: 3-(Difluoromethyl)-8-methyl-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine. Pd(dppf)Cl₂ (11.1 g, 15.2 mmol) was added to a mixture of 7-bromo-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 38, 40.0 g, 152 mmol), potassium vinyl trifluoroborate (40.9 g, 305 mmol) and K₃PO₄ (97.2 g, 457 mmol) in H₂O (100 mL) and 1,4-dioxane (400 mL) at 25° C. The mixture was heated to 80° C. and stirred for 1 hour under Na.

The brownish suspension was filtered, the filtrate was poured into H₂O (200 mL) and this aqueous suspension was extracted with DCM (300 mL×3). These extractions resulted in several organic solvent fractions which were combined and washed with brine (300 mL×3), dried with anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The product was triturated with petroleum ether (300 mL) and filtered, dried under vacuum to afford the title compound (30 g, 89%) as an off white solid.

Step B: 3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. K₂OsO₄.2H₂O (2.11 g, 5.74 mmol) was added to a solution consisting of 3-(difluoromethyl)-8-methyl-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (30.0 g, 143 mmol) in 1,4-dioxane (450 mL) and H₂O (450 mL) at 25° C., and then NaIO₄ (92.0 g, 430 mmol) was added. The resulting suspension was stirred at 25° C. for 2 hours then filtered and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was diluted with water and the aqueous phase was extracted with CH₂Cl₂ (500 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (500 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was triturated with petroleum ether (500 mL), then the solvent was filtered off and the solid was dried in a vacuum oven to afford the title compound (20.6 g, 67%) as an off white solid. MS (ESI): mass calcd. for C₉H₇F₂N₃O, 211.1; m/z found, 211.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.55 (s, 1H), 8.28 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.40-7.17 (m, 1H), 3.12 (s, 3H).

Intermediate 46: 5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine

Step A: (5-Bromo-2-methylpyridin-3-yl)methanol. NaBH₄ (9.40 g, 248 mmol) was added in portions to a solution of ethyl 5-bromo-2-methylnicotinate (20.2 g, 82.8 mmol) and MeOH (100 mL) at 0° C. The resulting mixture was stirred for 4 hours with gradual warming to room temperature. The mixture was quenched with H₂O (80 mL) and extracted with dichloromethane (120 mL×3). These extractions resulted in several organic solvent fractions which were combined, and dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 100:0 to 4:1, gradient elution) to afford the title compound (14.2 g) as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=2.0 Hz, 1H), 7.86 (d, J=1.3 Hz, 1H), 5.47 (t, J=5.5 Hz, 1H), 4.50 (d, J=5.5 Hz, 2H), 2.34 (s, 3H).

Step B: 5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine. TBSCl (14.5 g, 96.2 mmol) was added to a solution of (5-bromo-2-methylpyridin-3-yl)methanol (13 g, 64 mmol), 1H-imidazole (13.1 g, 192 mmol), and dichloromethane (120 mL). The mixture was stirred at room temperature for 20 minutes. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (60 mL). The combined organic extracts were concentrated to dryness under reduced pressure and purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 100:0 to 10:1, gradient elution) to afford the title compound (16.8 g). The still impure product (16.8 g) was combined with another batch prepared from (5-bromo-2-methylpyridin-3-yl)methanol (14.2 g, 70.3 mmol) to give a total of 35.4 g which was dissolved in ethyl acetate and washed with saturated aqueous NaHCO₃(200 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was further purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 100:0 to 10:1, gradient elution) and further purified by preparative HPLC using a Phenomenex Synergi Max-RP, 250 mm×50 mm×10 μm column (eluent: 50% to 99% (v/v) CH₃CN and H₂O with 10 mM NH₄HCO₃) to afford the title compound. The product was suspended in water (50 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (26 g, 58%). MS (ESI): mass calcd. for C₁₃H₂₂BrNOSi, 315.1; m/z found, 316 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=2.2 Hz, 1H), 7.83 (d, J=2.2 Hz, 1H), 4.67 (s, 2H), 2.35 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6H).

Intermediate 47: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridine

Step A: 4-Iodo-5-methylpyridin-2(1H)-one. Concentrated HCl (200 mL) was added to 2-fluoro-4-iodo-5-methylpyridine (100 g, 422 mmol) in 1,4-dioxane: water (1:1, 400 mL). The resulting mixture was heated to 100° C. for 2 hours and then cooled to room-temperature. The reaction was then quenched with water (400 mL) and stirred at room-temperature for 1 hour. The mixture was then cooled to 0° C., and the solids were isolated via filtration. The filter cake was washed with diethyl ether (100 mL) before drying under reduced pressure to afford the title compound (79 g, 80%). MS (ESI): mass calcd. for C₆H₆INO, 234.9; m/z found, 235.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (s, 1H), 7.23 (s, 1H), 2.10 (s, 3H).

Step B: Methyl 5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate. 4-Iodo-5-methylpyridin-2(1H)-one (59.5 g, 253 mmol), MeOH (1 L), and K₂CO₃ (35.0 g, 253 mmol) were added to a 2 L hydrogenation bottle. The resultant mixture was purged with Na for 5 minutes and then treated with Pd(OAc)₂ (11.4 g, 50.8 mmol) and dcpp.2HBF₄ (31.0 g, 50.6 mmol). The resultant mixture was stirred under CO (50 psi) at 80° C. for 36 hours. The suspension was filtered through a pad of diatomaceous earth and the filtrate concentrated to dryness under reduced pressure. The residue was triturated with ethyl acetate (500 mL) and the solids isolated by filtration. The filter cake was washed with ethyl acetate (50 mL) before drying under reduced pressure to afford the title compound (58 g), which was used in the next step without further purification.

Step C: Methyl 2-bromo-5-methylisonicotinate. POBr₃ (222.3 g, 775.4 mmol) was added to a solution of 5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (45.0 g) in toluene (500 mL). The resulting mixture was heated to 120° C. for 15 hours before cooling to room-temperature. The mixture was combined with another batch prepared from methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (13.0 g) and the resulting mixture was poured into ice/water (500 mL). The pH of resultant solution was adjusted to pH=8 with aqueous NaOH (5 N). and then the solution was extracted with ethyl acetate (500 mL×2). These extractions resulted in several organic solvent fractions which were combined, washed with brine (400 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 100:1 to 20:1, gradient elution) to afford the title compound (18 g) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.39-8.23 (m, 1H), 7.89 (s, 1H), 3.94 (s, 3H), 2.51 (s, 3H).

Step D: (2-Bromo-5-methylpyridin-4-yl)methanol. NaBH₄ (5.92 g, 157 mmol) was added to a solution of methyl 2-bromo-5-methylisonicotinate (18 g, 78 mmol) in MeOH (400 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour before quenching with H₂O (50 mL). The solvent was removed under reduced pressure and the resulting mixture was extracted with ethyl acetate (150 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (17 g) as a white solid. MS (ESI): mass calcd. for C₇H₈BrNO, 200.9; m/z found, 201.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 7.54 (s, 1H), 5.55 (br s, 1H), 4.51 (s, 2H), 2.18-2.09 (m, 3H).

Step E: 2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridine. TBSCl (7.76 g, 51.5 mmol) was added to a solution of (2-bromo-5-methylpyridin-4-yl)methanol (8.00 g, 39.6 mmol), 1H-imidazole (8.08 g, 119 mmol), and dichloromethane (100 mL). The resulting mixture was stirred at room-temperature for 1 hour. The mixture was combined with another batch prepared from (2-bromo-5-methylpyridin-4-yl)methanol (1.6 g, 7.9 mmol). The combined mixture was concentrated to dryness under reduced pressure to give a residue that was purified by preparative HPLC using a SANPONT C₁₈, 250 mm×80 mm×10 μm column (eluent: 70% to 100% (v/v) CH₃CN and H₂O with 10 mM NH₄HCO₃). The fractions that contained the desired product were collected, suspended in water (25 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (10 g, 67%) as a white solid. MS (ESI): mass calcd. for C₁₃H₂₂BrNOSi 315.1 m/z found 316.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.59 (s, 1H), 4.64 (s, 2H), 2.15 (s, 3H), 0.97 (s, 9H), 0.14 (s, 6H).

Intermediate 48: Methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: 5-(Hydroxy(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl)-2-methylbenzyl pivalate. To a mixture of 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (Intermediate 28, 2.00 g, 8.73 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl pivalate (Intermediate 42, 3.80 g, 11.4 mmol), and K₂CO₃ (3.74 g, 27.1 mmol) in THF was added tri(1-naphthyl)phosphine (106 mg, 0.60 mmol) and palladium II chloride (285 mg, 0.67 mmol). After heating at 60° C. for 24 hours, the reaction mixture was cooled, poured into water and extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-60% ethyl acetate/hexanes) to afford the title compound (1.90 g, 50.0%). MS (ESI): mass calcd. for C₂₂H₂₄F₃N₃O₃, 435.2; m/z found, 436.1 [M+H]⁺.

Step B: 5-(Chloro-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl)-2-methylbenzyl pivalate. To a solution of 5-(hydroxy(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl)-2-methylbenzyl pivalate (1.80 g, 4.13 mmol) in DCM (50 mL) was added dropwise thionyl chloride (3.50 mL, 47.8 mmol). After 24 hours the reaction mixture was slowly added to saturated aqueous bicarbonate and extracted with diethyl ether. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-50% ethyl acetate/hexanes) to afford the title compound (1.40 g, 75%). MS (ESI): mass calcd. for C₂₂H₂₃ClF₃N₃O₂, 453.1; m/z found, 454.1 [M+H]⁺.

Step C: Methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a mixture of 5-(chloro-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)methyl)-2-methylbenzyl pivalate (1.10 g, 2.42 mmol), dimethylketene methyl trimethylsilyl acetal (1.61 mL, 7.93 mmol) in DCM (32 mL) was added indium III bromide (200 mg, 0.56 mmol). After 18 hours the reaction was poured into saturated aqueous sodium bicarbonate and extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-50% ethyl acetate/hexanes) to afford the title compound (760 mg, 60%). MS (ESI): mass calcd. for C₂₇H₃₂F₃N₃O₄, 519.2; m/z found, 520.2 [M+H]⁺.

Step D: 3-(3-(Hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluormethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. A solution of sodium methoxide in methanol (1.0 mL, 4.37 mmol, 25% w/w) was added to a solution of methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (760 mg, 1.46 mmol) in methanol and stirred for 2 hours. The reaction was poured into saturated aqueous ammonium chloride and extracted three times with DCM. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0-80% ethyl acetate/hexanes) to afford the title compound (630 mg, 99%). An alternative preparation of this compound is described in the preparation of Intermediate 48, steps A-I. MS (ESI): mass calcd. for C₂₇H₃₂F₃N₃O₄, 435.2; m/z found, 436.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.3 Hz, 1H), 7.27 (d, J=7.4 Hz, 2H), 7.12 (dd, J=7.8, 2.1 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 5.03 (t, J=5.4 Hz, 1H), 4.76 (s, 1H), 4.43 (d, J=5.4 Hz, 2H), 3.52 (s, 3H), 2.68 (s, 3H), 2.18 (s, 3H), 1.33 (s, 3H), 1.28 (s, 3H).

Intermediate 49: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

Step A: (3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. A mixture of 3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (Intermediate 19, 0.5 g, 2.4 mmol), tert-butyldimethyl((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane (Intermediate 45, 1.3 g, 3.5 mmol), palladium (II) chloride (22 mg, 0.1 mmol), potassium carbonate (1.0 g, 7.3 mmol), and tri-1-naphthylphosphine (57 mg, 0.1 mmol) were charged to a reaction vessel, followed by addition of THF (15 mL). The vial was caped and degassed by bubbling argon through the reaction for 5 minutes, then the reaction was stirred overnight in a pre-heated block at 75° C. The reaction was cooled to room temperature, then filtered through diatomaceous earth and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (0.9 g, 85%). MS (ESI): mass calcd. for C₂₃H₃₁F₂N₃O₂Si, 447.2; m/z found, 448.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J=7.2 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20 (dd, J=7.7, 2.0 Hz, 1H), 7.15 (s, 1H), 7.09-7.02 (m, 1H), 6.08 (s, 1H), 4.61 (s, 2H), 3.26 (s, 1H), 2.57 (s, 3H), 2.17 (s, 3H), 0.80 (s, 9H), 0.00 (d, J=4.7 Hz, 6H).

Step B: 7-((3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. Thionyl chloride (1.6 mL, 23 mmol) was added to a solution of (34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (7.8 g, 17 mmol) and 2,6-di-tert-butylpyridine (7.8 ml, 35 mmol) in DCM (86 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to provide the title compound (7.5 g, 92%). MS (ESI): mass calcd. for C₂₃H₃₀ClF₂N₃O Si, 465.2; m/z found, 466.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J=7.3 Hz, 1H), 7.42-7.36 (m, 1H), 7.31 (s, 1H), 7.26-7.03 (m, 4H), 6.42 (s, 1H), 4.62 (s, 2H), 4.08 (q, J=7.1 Hz, 1H), 2.74 (d, J=0.7 Hz, 3H), 2.19 (s, 3H), 0.79 (s, 9H), 0.29-0.22 (m, 6H).

Step C: Methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (16 ml, 79 mmol) was added to a solution of 7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (7.5 g, 16 mmol) in DCM (80 ml). Indium(III) bromide (1.7 g, 4.9 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was filtered, concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (6.0 g, 70%). MS (ESI): mass calcd. for C₂₈H₃₉F₂N₃O₃Si, 531.3; m/z found, 532.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=7.3 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.18 (s, 1H), 7.14-7.06 (m, 1H), 7.06-6.96 (m, 2H), 4.79 (s, 1H), 4.60 (s, 2H), 3.54 (s, 3H), 2.73-2.67 (m, 3H), 2.16 (s, 3H), 1.39 (s, 3H), 1.32 (s, 3H), 1.23 (t, J=7.1 Hz, 0H), 0.83 (s, 9H), 0.00 (dd, J=16.9, 5.9 Hz, 6H).

Step D: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 23 ml, 23 mmol) was added to a solution of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (6.0 g, 11 mmol) in THF (62 ml). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH₄Cl, then extracted twice with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, concentrated to and purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (4.6, 98%). MS (ESI): mass calcd. for C₂₂H₂₅F₂N₃O₃, 417.2; m/z found, 418.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=7.3 Hz, 1H), 7.29 (d, J=4.7 Hz, 1H), 7.18 (d, J=7.7 Hz, 2H), 7.09 (d, J=1.3 Hz, 2H), 4.81 (s, 1H), 4.68 (d, J=3.8 Hz, 2H), 4.13 (q, J=7.1 Hz, 1H), 3.58 (s, 3H), 2.73 (s, 3H), 2.28 (s, 3H), 1.35 (s, 6H).

Intermediate 50: Methyl 3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: (44(Tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. n-Butyllithium (2.0 M, 3.1 ml, 6.2 mmol) was added dropwise to a stirring solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridine (Intermediate 47, 2.0 g, 6.3 mmol) in THF (14 ml) at −78° C. under nitrogen. This reaction was stirred at −78° C. for 2 minutes to prepare the lithiate reaction mixture. A solution 3-(trifluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (Intermediate 28, 1.2 g, 5.1 mmol) in THF (10 ml) was added to the lithiate reaction mixture dropwise. The resulting reaction mixture was stirred at −78° C. for 5 minutes. The reaction was then quenched with saturated aqueous NaHCO₃, and then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to provide the title compound (1.0 g, 42%). MS (ESI): mass calcd. for C₂₂H₂₉F₃N₄O₂Si, 466.2; m/z found, 467.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (t, J=0.8 Hz, 1H), 8.05-7.99 (m, 1H), 7.25 (s, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.19 (s, 1H), 5.94 (s, 1H), 4.65 (dd, J=15.6, 1.1 Hz, 1H), 4.60 (dd, J=15.6, 1.0 Hz, 1H), 2.86 (s, 3H), 2.20 (s, 3H), 2.06 (s, 1H), 1.27 (t, J=7.1 Hz, 1H), 0.78 (s, 9H), 0.84-0.72 (m, 1H), 0.05 (s, 3H).

Step B: 7-((4-(((Tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. Thionyl chloride (0.3 mL, 4.2 mmol) was added to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (1.5 g, 3.2 mmol) and 2,6-di-tert-butylpyridine (1.4 ml, 6.4 mmol) in DCM (16 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to provide the title compound (1.0 g, 64% yield). MS (ESI): mass calcd. for C₂₂H₂₈ClF₃N₄O Si, 484.2; m/z found, 485.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (t, J=0.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.62 (s, 1H), 7.25 (d, J=7.3 Hz, 1H), 6.35 (s, 1H), 4.58 (d, J=1.0 Hz, 2H), 3.98 (q, J=7.1 Hz, 1H), 2.71 (d, J=0.7 Hz, 3H), 2.08 (s, 3H), 1.12 (t, J=7.1 Hz, 1H), 0.80 (s, 9H), 0.86-0.74 (m, 1H), 0.05 (s, 3H).

Step C: Methyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (6.1 ml, 30 mmol) was added to a solution of 7-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (3.0 g, 6.2 mmol) in DCM (31 ml). Indium(III) bromide (0.67 g, 1.9 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was filtered, concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (0.5 g, 15% yield). MS (ESI): mass calcd. for C₂₇H₃₇F₃N₄O₃Si, 550.2; m/z found, 551.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.22 (d, J=0.8 Hz, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.06 (s, 1H), 5.04 (s, 1H), 4.60-4.49 (m, 2H), 3.59 (s, 3H), 2.86 (s, 3H), 2.11 (s, 3H), 2.01 (s, 1H), 1.28 (s, 3H), 1.22 (t, J=7.1 Hz, 1H), 0.74 (s, 9H), 0.76-0.70 (m, 1H), 0.14-0.07 (m, 6H).

Step D: Methyl 3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Tetrabutylammonium fluoride (1 M in THF, 1.4 ml, 1.4 mmol) was added to a solution of methyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (0.5 g, 0.9 mmol) in THF (5 ml). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH₄Cl, then extracted twice with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (280 mg, 71% yield). MS (ESI): mass calcd. for C₂₁H₂₃F₃N₄O₃, 436.2; m/z found, 437.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=0.8 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.23 (s, 1H), 5.00 (s, 1H), 4.71-4.66 (m, 2H), 3.60 (s, 4H), 2.86-2.82 (m, 3H), 2.19 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

Intermediate 51: Methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate

Step A: (54(Tert-butyldimethyl silyl)oxy)methyl)-6-methylpyridin-3-yl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. n-Butyllithium (2.5 M, 9.2 ml, 23 mmol) was added dropwise to a stirring solution of 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (Intermediate 46, 4.8 g, 15 mmol) in THF (20 ml) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 2 minutes to prepare the lithiate reaction mixture. A solution 1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (Intermediate 22, 2.9 g, 15 mmol) in THF (10 ml) was added to the lithiate reaction mixture dropwise. The reaction was stirred at −78° C. for 5 minutes. The reaction was quenched with saturated aqueous NaHCO₃, and then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to provide the title compound (4.0 g, 61%). MS (ESI): mass calcd. for C₂₃H₃₄N₄O₂Si, 426.2; m/z found, 427.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.25 (dd, J=8.3, 1.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.04 (s, 1H), 5.64 (s, 1H), 4.79 (d, J=0.9 Hz, 2H), 4.53 (q, J=7.3 Hz, 2H), 2.80 (s, 3H), 2.28 (s, 3H), 1.47 (t, J=7.3 Hz, 3H), 0.81 (s, 9H), 0.00 (d, J=1.1 Hz, 6H).

Step B: Methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Trichloroacetonitrile (1.4 g, 9.4 mmol) and DBU (0.1 g, 0.7 mmol) were added to a solution of (5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (2.0 g, 4.7 mmol) in ACN (25 ml). The reaction was stirred at room temperature under nitrogen for 1 hour. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.6 g, 9.4 mmol) was then added to the reaction, followed by trifluoromethanesulfonamide (0.7 g, 2.3 mmol), and the reaction was stirred at room temperature under nitrogen for 3 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-50% EtOAc/hexanes, gradient elution) to provide the title compound that was carried forward without further purification (1.5 g, 63% yield). MS (ESI): mass calcd. for C₂₈H₄₂N₄O₃Si, 510.3; m/z found, 511.3 [M+H]⁺.

Step C: Methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 11.7 ml, 11.7 mmol) was added to a solution of methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (3.0 g, 5.8 mmol) and 3 drops of DMF in THF (60 ml). The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure. The product was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to provide the title compound (1.8 g, 77% yield). MS (ESI): mass calcd. for C₂₂H₂₈N₄O₃, 396.2; m/z found, 397.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=2.3 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 4.83 (s, 1H), 4.69-4.56 (m, 4H), 4.35 (s, 1H), 3.50 (s, 3H), 2.74 (s, 3H), 2.37 (s, 3H), 1.57 (t, J=7.3 Hz, 3H), 1.36 (s, 3H), 1.29 (s, 3H).

Intermediate 52: 2-hydrazinyl-4-iodo-3-methylpyridine

A mixture of hydrazine hydrate (47.0 mL, 630 mmol) and 2-fluoro-4-iodo-3-methylpyridine (23.39 g, 98.69 mmol) was stirred at 60° C. for 24 hours. The mixture was cooled to room temperature and then aqueous NaOH solution (60 mL, 3M) and water (60 mL) were added to the mixture and the suspension was stirred at 25° C. for 45 minutes. The solid was filtered, washed with water, and the solid was dried under reduced pressure to afford the title compound as a white solid (20.4 g, 83%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₆H₈IN₃, 249.05; m/z found, 250 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (d, J=5.3 Hz, 1H), 7.44 (s, 1H), 7.03 (d, J=5.3 Hz, 1H), 4.17 (s, 2H), 2.19-2.11 (m, 3H).

Intermediate 53: 7-iodo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

TFAA (53.0 mL, 375 mmol) was slowly added to a mixture of 2-hydrazinyl-4-iodo-3-methylpyridine (Intermediate 52, 20.4 g, 81.9 mmol) in toluene (40 mL). The mixture was heated to 60° C. for 22 hours under an atmosphere of nitrogen. The solvents were removed under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous NaHCO₃ solution, brine, dried and concentrated under reduced pressure. The residue was triturated with DCM/hexanes to afford the title compound as a white solid. MS (ESI): mass calcd. for C₈H₅F₃IN₃, 327.0; m/z found, 328.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=7.2 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.68 (d, J=0.8 Hz, 3H).

Intermediate 54: 7-Bromo-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine

Step A: 4-Bromo-2-hydrazinyl-3-methylpyridine. Hydrazine hydrate (391 mL, 8.04 mol) was added to 4-bromo-2-fluoro-3-methylpyridine (240 g, 1.3 mol) and the white suspension was heated to 60° C. for 7 hours. The white suspension was concentrated under reduced pressure and the resulting white precipitate was collected by filtration. The solid was triturated with methyl tert-butyl ether (200 mL) to provide the title compound (255 g, 99.7% yield) as a white solid, which was used in the next step without further purification, MS (ESI): mass calcd. for C₆H₈BrN₃, 203.0; m/z found, 203.8 [M+H]⁺.

Step B: 7-Bromo-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. Cyclopropanecarbaldehyde (28.5 mL, 381 mmol) was added to a solution of 4-bromo-2-hydrazinyl-3-methylpyridine (70.0 g, 346 mmol) in EtOH (700 mL), and the light yellow mixture was stirred at 30° C. for 3 hours. H₂O (175 mL), CuBr₂ (1.62 mL, 34.6 mmol), and oxone (255.5 g, 415.7 mmol) were then added portion-wise and the resulting yellow solution was stirred for an additional 3 hours at 30° C. The mixture was filtered and the filtrate was concentrated under reduced pressure. Water (200 mL) was added to the reaction mixture, the pH was adjusted to 8 with saturated aqueous NaHCO₃, and the aqueous layer was extracted with dichloromethane (200 mL×3). These extractions resulted in several organic solvent fractions which were combined and washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was triturated with EtOAc (200 mL) and filtered. The resulting solid cake was dried under reduced pressure to afford the title compound (48 g, 52% yield) as a solid, which was used without further purification, MS (ESI): mass calcd. for C₁₀H₁₀BrN₃, 253.0; m/z found, 253.8 [M+H]⁺.

Intermediate 55: Methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

Step A: 3-Cyclopropyl-8-methyl-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine. A mixture of 7-bromo-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 54, 48.0 g, 190 mmol), potassium trifluoro(vinyl)borate (25.5 g, 190 mmol), potassium phosphate (121.6 g, 573.1 mmol), and Pd(dppf)Cl₂ (16.1 g, 19.8 mmol) in EtOH (720 mL) was degassed and purged with nitrogen 3 times and then the suspension was stirred at 85° C. for 12 hours under nitrogen. The mixture was concentrated under reduced pressure and the resulting residue was filtered through diatomaceous earth, and rinsed with DCM (200 mL). The filtrate was concentrated, and purified by FCC (5% MeOH/DCM) to afford the title compound (38.0 g, 80%, 80% purity). MS (ESI): mass calcd. for C₁₂H₁₃N₃, 199.1; m/z found, 200.2 [M+H]⁺.

Step B: 3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. Potassium osmate (2.44 g, 6.62 mmol) was added to a solution of 3-cyclopropyl-8-methyl-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (33.0 g, 166 mmol), dioxane (825 mL) and H₂O (825 mL). Then sodium periodate (113.3 g, 530 mmol) was added and the suspension was stirred at 30° C. for 2 hours. The reaction mixture was filtered through a plug of diatomaceous earth and the filtrate was concentrated under reduced pressure. The resulting residue was then diluted by addition of H₂O (200 mL) and the aqueous layer was extracted with DCM (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The product was triturated with DCM/hexanes (50 ml/250 ml) and further purified by flash column chromatography (5% EtOAc/DCM) to afford the title compound (20.9 g, 62%). MS (ESI): mass calcd. for C₁₁H₁₁N₃O, 201.1; m/z found, 202.0 [M+H]⁺.

Step C: (3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. 3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (3.0 g, 15 mmol), tert-butyldimethyl((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane (Intermediate 43, 6.9 g, 18 mmol), palladium (II) chloride (0.26 g, 1.5 mmol), potassium carbonate (6.2 g, 45 mmol), and tri-1-naphthylphosphine (0.93 g, 2.2 mmol) were charged to a flask. The flask was evacuated and back-filled with nitrogen. THF (75 ml) was degassed with argon, then added via syringe. Argon was bubbled through the reaction mixture for 1 minute, then the reaction was stirred overnight in a pre-heated block at 75° C. under a reflux condenser and nitrogen. The reaction was cooled to room temperature, then filtered through diatomaceous earth and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (dry loaded with silica gel, 0-5% MeOH/DCM, gradient elution) to afford the title compound that was carried forward without further purification (0.66 g, 10%). MS (ESI): mass calcd. for C₂₅H₃₅N₃O₂Si, 437.2; m/z found, 438.3 [M+H]⁺. An alternative method that was used to prepare (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol is shown below: 3-Cyclopropyl-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 162, 5.05 g, 16.9 mmol) in 2-methyltetrahydrofuran (60 mL) was cooled in an ice bath under nitrogen, resulting in a suspension. Isopropylmagnesium chloride lithium chloride complex solution (1.3 M, 17 mL, 22 mmol) was added dropwise to the suspension and the reaction was removed from the ice bath and allowed to warm to room temperature for 30 minutes. 3(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylbenzaldehyde (Intermediate 163, 5.34 g, 20.2 mmol) was then added to the reaction via syringe using 2-methyltetrahydrofuran (4 mL). The suspension was stirred for 2 hours and became an orange solution, then was diluted with water and ethyl acetate. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-10% MeOH/DCM) to afford the title compound (5.99 g, 81% yield). MS (ESI): mass calcd. for C₂₅H₃₅N₃O₂Si, 437.2; m/z found, 438.3 [M+H]⁺.

Step D: 74(3-(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)chloromethyl)-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. Thionyl chloride (0.2 mL, 3 mmol) was added to a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (0.59 g, 1.3 mmol) and 2,6-di-tert-butylpyridine (0.7 ml, 3.1 mmol) in DCM (7 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (dry loaded with silica gel, 0-50% ethyl acetate/hexanes, gradient elution) to provide the title compound (200 mg, 32%). MS (ESI): mass calcd. for C₂₅H₃₄ClN₃OSi, 455.2; m/z found, 456.2 [M+H]⁺.

Step E: Methyl 3-(34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.6 ml, 3.0 mmol) was added to a solution of 74(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)chloromethyl)-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (267 mg, 0.585 mmol) in DCM (3 mL). Indium(III) bromide (114 mg, 0.322 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was filtered, concentrated under a stream of nitrogen, and purified by flash column chromatography (0-10% MeOH/EtOAc, gradient elution) to afford the title compound (197 mg, 64%). MS (ESI): mass calcd. for C₃₀H₄₃N₃O₃Si, 521.3; m/z found, 522.3 [M+H]⁺.

Step F: Methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 0.5 ml, 0.5 mmol) was added to a solution of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-2,2-dimethylpropanoate (197 mg, 0.38 mmol) in THF (2 ml). The reaction was stirred at room temperature for 1 hour. Additional tetrabutylammonium fluoride (1 M in THF, 0.1 ml, 0.1 mmol) was added and the reaction was stirred at room temperature for an additional 3.5 hours. The reaction was quenched with saturated aqueous NH₄Cl, then extracted twice with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (145 mg, 94%) which was used without further purification. MS (ESI): mass calcd. for C₂₄H₂₉N₃O₃, 407.2; m/z found, 408.2 [M+H]⁺.

Intermediate 56: Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate

Step A: 1-Cyclopropyl-4-methyl-5-vinyl-1H-benzo[d][1,2,3]triazole. A mixture of 5-bromo-1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 29, 17 g, 67.4 mmol), potassium trifluoro(vinyl)borate (18.1 g, 135 mmol), potassium phosphate (42.9 g, 202 mmol), and Pd(dppf)Cl₂ (2.75 g, 3.37 mmol) were added to a flask, which was then evacuated and back-filled with nitrogen. 1,4-Dioxane (170 ml) and water (30 ml) were bubbled with nitrogen for 10 minutes, then added to the solid reagents. The reaction mixture was heated to 100° C. under a reflux condenser and nitrogen for 4 hours. The reaction was then cooled to room temperature and filtered through diatomaceous earth, rinsing with EtOAc. The filtrate was washed with brine, then dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by FCC (0-20% EtOAc/hexanes) to afford the title compound that was carried forward without further purification (2.1 g, 52%). MS (ESI): mass calcd. for C₁₂H₁₃N₃, 199.1; m/z found, 200.2 [M+H]⁺.

Step B: 1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde. Potassium osmate (2.22 g, 6.0 mmol) was added to a solution of 1-cyclopropyl-4-methyl-5-vinyl-1H-benzo[d][1,2,3]triazole (30 g, 150 mmol), 1,4-dioxane (750 ml) and H₂O (750 ml). Then sodium periodate (103 g, 482 mmol) was added. The suspension was stirred at 25° C. for 2 hours. The reaction mixture was filtered through a plug of diatomaceous earth, rinsing with EtOAc. The filtrate was extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were washed with brine, combined, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by FCC (10-30% EtOAc/hexanes) to provide a residue. This residue was then stirred with hexanes (100 ml) for 2 hours, filtered, and the filter cake was dried under reduced pressure to afford the title compound (21.2 g, 70%). MS (ESI): mass calcd. for C₁₁H₁₁N₃O, 201.1; m/z found, 201.9 [M+H]⁺.

Step C: (5-(((Tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. n-Butyllithium (1.6 M, 9 ml, 14 mmol) was added dropwise to a solution of 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (Intermediate 46, 4.05 g, 12.8 mmol) in THF under nitrogen (95 ml) which was cooled to −78° C. to prepare the lithiate reaction mixture. In a separate flask, 1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (2.81 g, 14 mmol) was mixed with THF (70 ml) and the resulting suspension was stirred and heated to form a solution. After all the solids had dissolved, this 1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde solution was cooled to room temperature, then added to the lithiate reaction mixture as a stream. The resulting reaction mixture was then removed from the −78° C. bath and allowed to warm to room temperature for 30 minutes. The reaction was quenched with saturated aqueous NaHCO₃, and then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (dry loaded with silica gel, 0-5% MeOH/DCM, gradient elution) to provide the title compound (1.96 g, 35%). MS (ESI): mass calcd. for C₂₄H₃₄N₄O₂Si, 438.2; m/z found, 439.3 [M+H]⁺.

Step D: Methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Trichloroacetonitrile (0.9 ml, 9 mmol) and DBU (0.15 ml, 1 mmol) were added to a solution of (5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (1.91 g, 4.4 mmol) in ACN (22 ml). The reaction was stirred at room temperature under nitrogen for 1 hour. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (4.4 ml, 22 mmol) was then added to the reaction, followed by trifluoromethanesulfonamide (1.28 g, 4.6 mmol), and the reaction was stirred at room temperature under nitrogen for 3 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-50% EtOAc/hexanes, gradient elution) to provide the title compound that was carried forward without further purification (1.5 g, 66%). MS (ESI): mass calcd. for C₂₉H₄₂N₄O₃Si, 522.3; m/z found, 523.4 [M+H]⁺.

Step E: Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 5.7 ml, 5.7 mmol) was added to a solution of methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (1.5 g, 2.9 mmol) and 3 drops of DMF in THF (29 ml). The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure. The product was purified by flash column chromatography (0-100% EtOAc/hexanes, gradient elution) to provide the title compound (0.77 g, 66%). MS (ESI): mass calcd. for C₂₃H₂₈N₄O₃, 408.2; m/z found, 409.2 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ 8.33-8.28 (m, 1H), 7.63-7.56 (m, 2H), 7.42 (d, J=8.7 Hz, 1H), 4.82 (s, 1H), 4.68-4.57 (m, 2H), 3.77-3.66 (m, 1H), 3.51 (s, 3H), 3.26 (s, 1H), 2.74 (s, 3H), 2.40 (s, 3H), 1.39-1.23 (m, 10H).

Intermediate 57: 6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde

Step A: Methyl 6-chloro-3-methylpicolinate. Thionyl chloride (208 g, 1.75 mol) was added to a solution of 6-chloro-3-methylpicolinic acid (200 g, 1.17 mol) in methanol (300 mL) and the reaction mixture was warmed to 65° C. After 3 hours, the reaction mixture was concentrated under reduced pressure, and saturated aqueous NaHCO₃ solution (1 L) was added.

The aqueous layer was extracted twice with ethyl acetate which resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound as a dark-brown solid (210 g, 97%). ¹H NMR (400 MHz, CDCl₃) 7.57 (d, J=8.0 Hz, 1H) 7.36 (d, J=8.0 Hz, 1H) 3.95 (s, 3H) 2.53 (s, 3H).

Step B: (6-Chloro-3-methylpyridin-2-yl)methanol. Sodium borohydride (257 g, 6.79 mol) was added to a stirring solution of methyl 6-chloro-3-methylpicolinate (210 g, 1.13 mol) in THF (200 mL) and the mixture was warmed to 66° C. After 30 minutes, the mixture was cooled to room temperature and methanol (50 mL) was added dropwise. The resulting solution was warmed to 66° C. After 2 hours, the reaction mixture was cooled to room temperature, saturated aqueous NH₄Cl solution was added and the biphasic mixture was stirred for 1.5 hours. The mixture was filtered and the aqueous layer was extracted twice with ethyl acetate. This resulted in several organic solvent fractions which were combined, washed with saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound as a light yellow oil (140 g, 78%). ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.33 (d, J=8.0 Hz, 1H), 7.07-7.05 (d, J=8 Hz, 1H), 4.57 (s, 2H), 2.12 (s, 3H).

Step C: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloro-3-methylpyridine. TBSCl (36.8 g, 244 mmol) was added to a stirring solution of (6-chloro-3-methylpyridin-2-yl)methanol (35 g, 222 mmol) and imidazole (30.2 g, 444 mmol) in dichloromethane (450 mL). After 16 hours, dichloromethane (400 mL) was added and the mixture was washed sequentially with water and saturated aqueous NaCl solution. The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide a residue. The residue was purified by flash column chromatography (petroleum ether (containing 1% triethylamine)/ethyl acetate (50:1 to 5:1) gradient elution) to afford the title compound as a colorless liquid (58 g, 94%). MS (ESI): mass calcd. for C₁₃H₂₂ClNOSi, 271.1; m/z found, 271.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 7.39 (d, J=7.6 Hz, 1H) 7.12 (d, J=7.6 Hz, 1H) 4.75 (s, 2H) 2.36 (s, 3H) 0.87 (s, 9H) 0.07 (s, 6H).

Step D: Methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinate. A mixture containing 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-3-methylpyridine (65 g, 239 mmol), triethylamine (66.6 mL), and Pd(dppf)₂Cl₂ (17.5 g, 23.9 mmol) in DMF (350 mL) and methanol (350 mL) was stirred at 80° C. under a 50 psi atmosphere of carbon monoxide. After 16 hours, the reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. This mixture was washed with water and the aqueous layers were extracted with ethyl acetate. This resulted in several organic fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate containing 1% triethylamine) to afford the title compound as a light yellow solid (60 g, 84%). ¹H NMR (400 MHz, CDCl₃) 7.95 (d, J=7.6 Hz, 1H) 7.58 (d, J=7.8 Hz, 1H) 4.88 (s, 2H) 3.97 (s, 3H) 2.47 (s, 3H) 0.88 (s, 9H) 0.07 (s, 6H).

Step E. 6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde. A 1 M solution of DIBAL-H in dichloromethane (264 mL, 264 mmol) was added dropwise to a stirring mixture of methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinate (68 g, 219 mmol) in dichloromethane (1.5 L) at a rate that maintained an internal temperature of less than 60° C. After 2 hours, methanol (20 mL) was added and the reaction allowed to warm to room temperature. Saturated aqueous potassium sodium tartrate solution (1 L) was added and the resulting biphasic mixture was stirred for 1 hour. The mixture was extracted twice with dichloromethane which resulted in several organic solvent fractions which were combined, washed with saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to afford the title compound as a light yellow solid (33.1 g, 53%). MS (ESI): mass calcd. for C₁₄H₂₃NO₂Si, 265.2; m/z found, 266.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 10.03 (s, 1H) 7.81 (d, J=7.8 Hz, 1H) 7.62 (d, J=7.8 Hz, 1H) 4.91 (s, 2H) 2.50 (s, 3H) 0.90 (s, 9H) 0.09 (s, 6H).

Intermediate 58: ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

Step A: 1-chloro-3-(difluoromethyl)-2-nitrobenzene. Diethylamino sulfurtrifluoride (32.6 g, 202 mmol) was added to a 0° C. (ice/water) solution consisting of 3-chloro-2-nitrobenzaldehyde (15 g, 81 mmol) and dichloromethane (200 mL). The resultant mixture was stirred for 3 hours with gradual warming to room-temperature before quenching with H₂O (200 mL) and extracting with dichloromethane (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 20:1, gradient elution) to give the title compound (12 g, 64%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.06-7.95 (m, 1H), 7.86-7.77 (m, 2H), 7.42-7.11 (m, 1H).

Step B: N-(Cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline. 1-Chloro-3-(difluoromethyl)-2-nitrobenzene (2.0 g, 9.6 mmol) and cyclopropylmethanamine (10 mL) were added to a 20 mL sealed tube. The resultant mixture was stirred at 80° C. for 16 hours before cooling to room-temperature, quenching with water (60 mL), and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 5:1, gradient elution) to give the title compound (2.1 g, 90%). MS (ESI): mass calcd. for C₁₁H₁₂F₂N₂O₂ 242.1, m/z found 242.7 [M+H]⁺.

Step C: 4-Bromo-N-(cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline. N-(Cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline (2.1 g, 8.7 mmol), NBS (1.54 g, 8.65 mmol), and DMF (10 mL) were added to a 50 mL round-bottomed flask. The resultant mixture was stirred at room-temperature for 4 hours before quenching with water (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 5:1, gradient elution) to give the title compound (2.1 g, 68%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, J=9.0 Hz, 1H), 7.09-6.79 (m, 2H), 6.22 (t, J=5.6 Hz, 1H), 2.86 (t, J=6.2 Hz, 2H), 0.91-0.79 (m, 1H), 0.28-0.18 (m, 2H), 0.05-0.04 (m, 2H).

Step D: 4-Bromo-N¹-(cyclopropylmethyl)-3-(difluoromethyl)benzene-1,2-diamine. Zn (3.4 g, 52 mmol) was added to a solution of 4-bromo-N-(cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline (2.1 g, 6.5 mmol), NH₄Cl (5.6 g, 105 mmol), and THF (20 mL). The resultant mixture was stirred at room-temperature for 16 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (1×). The filtrate was concentrated to dryness under reduced pressure to afford the title product (1.8 g, 95%). MS (ESI): mass calcd. for C₁₁H₁₃BrF₂N₂ 290.0, m/z found 292.8 [M+H]⁺.

Step E: 5-Bromo-1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazole. A solution of NaNO₂ (5.7 g, 83 mmol) and H₂O (10 mL) were added to a 0° C. (ice/water) mixture of 4-bromo-N¹-(cyclopropylmethyl)-3-(difluoromethyl)benzene-1,2-diamine (8.0 g, 27 mmol), 4-methylbenzenesulfonic acid hydrate (18.3 g, 96.2 mmol), and CH₃CN (100 mL). The resultant mixture was stirred at 0° C. for 3 hours before quenching with aq. NaHCO₃(300 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 5:1) to give the title compound (6.2 g, 75%). MS (ESI): mass calcd. for C₁₁H₁₀BrF₂N₃ 301.0, m/z found 303.7 [M+H]⁺.

Step F: (E)-Ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. 5-Bromo-1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazole (2.0 g, 6.6 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (3.0 g, 13 mmol), and Na₂CO₃ (1.4 g, 13 mmol) were added to a 100 mL three-necked round-bottomed flask and the resulting mixture dissolved in 1,4-dioxane (30 mL) and H₂O (6 mL). The mixture was sparged with Na for 5 minutes and then treated with Pd(dppf)Cl₂ (484 mg, 0.661 mmol). The mixture was sparged with Na for another 5 minutes and then stirred and heated at 100° C. for 16 hours before cooling to room-temperature, quenching with water (60 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 20:1 to 5:1, gradient elution) to give the title compound (2.0 g, 80%) as a black solid. MS (ESI): mass calcd. for C₁₆H₁₇F₂N₃O₂ 321.1, m/z found 321.9 [M+H]⁺.

Step G: Ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. (E)-Ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (1.5 g, 4.7 mmol), (3-(hydroxymethyl)-4-methylphenyl)boronic acid (2.3 g, 14 mmol), aqueous KOH (5.6 mL, 1.0 M, 5.6 mmol), and 1,4-dioxane (20 mL) were added to a 100 mL round-bottomed flask. The mixture was sparged with Na for 5 minutes and then treated with chloro(1,5-cyclooctadiene)rhodium(I) dimer (230 mg, 0.47 mmol). The reaction mixture was stirred at room-temperature for 16 hours before quenching with H₂O (60 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (eluent: MeCN/water with 0.05% NH₃, 3:7 to 7:3, gradient elution). The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (510 mg, 24%). MS (ESI): mass calcd. for C₂₄H₂₇F₂N₃O₃ 443.20, m/z found 444.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.75 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.18-7.12 (m, 1H), 7.07-7.01 (m, 1H), 5.17-5.07 (m, 1H), 5.01 (t, J=5.3 Hz, 1H), 4.58 (d, J=7.3 Hz, 2H), 4.43-4.35 (m, 2H), 3.97-3.88 (m, 2H), 3.28-3.19 (m, 1H), 3.14-3.05 (m, 1H), 2.14 (s, 3H), 1.38-1.26 (m, 1H), 1.01 (t, J=7.2 Hz, 3H), 0.55-0.39 (m, 4H).

Intermediate 59: 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 3-(Nitromethyl)oxetan-3-ol. Et₃N (0.5 mL) was added drop-wise to a solution consisting of oxetan-3-one (10.0 g, 139 mmol) and MeNO₂ (25 mL). The resultant mixture was stirred at room-temperature for 16 hours before concentrating to dryness to give the product, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:1 gradient elution) to afford the title compound (15 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 4.76 (s, 2H), 4.68-4.59 (m, 4H), 4.26 (s, 1H).

Step B: 3-(Aminomethyl)oxetan-3-ol. Dry Pd/C (1.0 g, 10 wt. %, 0.95 mmol) was added to a solution of 3-(nitromethyl)oxetan-3-ol (10 g, 75 mmol) and ethanol (50 mL) under N₂. The resultant mixture was stirred under H₂ (1 atm) at room-temperature for 16 hours. The suspension was filtered through a pad of diatomaceous earth and the pad washed with ethanol (50 mL). The filtrate was concentrated to dryness under reduced pressure to afford the product (8 g), which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 5.52 (br s, 2H), 4.45 (d, J=6.6 Hz, 2H), 4.37-4.32 (m, 2H), 2.97 (s, 2H), 2.69 (s, 1H).

Step C: 2-Chloro-N-((3-hydroxyoxetan-3-yl)methyl)pyridine-3-sulfonamide. 2-Chloropyridine-3-sulfonyl chloride (10 g, 47 mmol) was added to a solution of 3-(aminomethyl)oxetan-3-ol (7.3 g), K₂CO₃ (7.8 g, 56 mmol), THF (90 mL), and H₂O (20 mL). The resultant mixture was stirred at room-temperature for 16 hours before concentrating to dryness under reduced pressure. The residue was dissolved water (30 mL) and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (7 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₉H₁₁ClN₂O₄S 278.01, m/z found 279.1[M+H]⁺.

Step D: 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine-1′,1′-dioxide. t-BuOK (7.1 g, 63 mmol) was added to a solution consisting of 2-chloro-N-((3-hydroxyoxetan-3-yl)methyl)pyridine-3-sulfonamide (6.5 g) and DMSO (24 mL). The resultant mixture was stirred while heating at 95° C. for 2 hours before cooling to room-temperature, diluting with water (20 mL), acidifying pH to 4 with 1 N HCl, and extracting with ethyl acetate (50 mL×4). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure, which was purified by preparative HPLC using a preparative HPLC (eluent: CH₃CN/H₂O with 0.225% HCOOH, 1:99 to 1:4 gradient elution) to afford pure product. The product was suspended in water (20 mL), the mixture was frozen using dry ice/acetone, and then lyophilized to dryness to afford the title compound (2.1 g). MS (ESI): mass calcd. for C₉H₁₀N₂O₄S 242.0, m/z found 243.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (dd, J=2.0, 4.9 Hz, 1H), 8.36 (br s, 1H), 8.16 (dd, J=2.0, 7.7 Hz, 1H), 7.50-7.35 (m, 1H), 4.40 (s, 4H), 3.90-3.77 (m, 2H).

Intermediate 60: ethyl 3-(4-difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate

Step A: 3-(Difluoromethyl)-N-methyl-2-nitroaniline. 1-Chloro-3-(difluoromethyl)-2-nitrobenzene (9.0 g, 43 mmol) and methanamine (30 mL, 33% purity in ethanol) were added to a 100 mL sealed tube. The resultant mixture was stirred at 70° C. for 16 hours before cooling to room-temperature and concentrating to dryness under reduced pressure to afford the title compound (10 g), which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.45 (m, 1H), 7.43-7.13 (m, 1H), 7.07 (d, J=7.3 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 3.01 (d, J=5.1 Hz, 3H).

Step B: 4-Bromo-3-(difluoromethyl)-N-methyl-2-nitroaniline. NBS (8.8 g, 49 mmol) was added to a solution of 3-(difluoromethyl)-N-methyl-2-nitroaniline (10.0 g, 49.5 mmol) and DMF (100 mL). The resultant mixture was stirred at room-temperature for 16 hours before pouring it into water (300 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate 1:0 to 5:1, gradient elution) to afford the title compound (13 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 8.00 (br s, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.06-6.80 (m, 1H), 6.78 (d, J=2.6 Hz, 1H), 5.63 (br s, 1H), 2.91 (d, J=5.1 Hz, 3H).

Step C: 4-Bromo-3-(difluoromethyl)-M-methylbenzene-1,2-diamine. Zn (22.3 g, 341 mmol) was added to a mixture of 4-bromo-3-(difluoromethyl)-N-methyl-2-nitroaniline (12.0 g, 42.7 mmol), NH₄Cl (36.5 g, 682 mmol), and THF (300 mL). The resultant mixture was stirred at room-temperature for 16 hours. The suspension was filtered through a pad of diatomaceous earth and the pad washed with ethyl acetate (200 mL). The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent:

petroleum ether/ethyl acetate, 50:1 to 10:1, gradient elution) to afford the title compound (9.5 g, 89%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.40-7.06 (m, 1H), 7.03-6.95 (m, 1H), 6.58 (d, J=8.6 Hz, 1H), 2.91-2.82 (m, 3H).

Step D: 5-Bromo-4-(difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazole. A solution consisting of NaNO₂ (7.4 g, 0.11 mol) and H₂O (20 mL) was added to a 0° C. (ice/water) mixture consisting of 4-bromo-3-(difluoromethyl)-M-methylbenzene-1,2-diamine (9.0 g, 36 mmol), p-toluenesulfonic acid monohydrate (23.9 g, 126 mmol), and CH₃CN (300 mL). The resultant mixture was stirred at 0° C. for 3 hours before quenching with sat. NaHCO₃(500 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 5:1, gradient elution) to afford the title compound (5.0 g, 47%). ¹H NMR (400 MHz, DMSO-d₆) δ (d, J=8.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.55 (t, J=52.4 Hz, 1H), 4.40-4.26 (m, 3H).

Step E: (E)-Ethyl 3-(4-(difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. 5-Bromo-4-(difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazole (3.2 g, 12 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (5.5 g, 24 mmol), and Na₂CO₃ (3.9 g, 37 mmol) were dissolved in 1,4-dioxane (100 mL) and H₂O (20 mL). The mixture was sparged with nitrogen for 5 minutes and then treated with Pd(dppf)Cl₂ (0.89 g, 1.2 mmol). The mixture was sparged with nitrogen for another 5 minutes and then stirred at 100° C. for 16 hours under nitrogen before cooling to room-temperature and diluting with ethyl acetate (100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 1:2, gradient elution) to afford the title compound (2.3 g, 93%). MS (ESI): mass calcd. for C₁₃H₁₃F₂N₃O₂ 281.1 m/z 281.9.

Step F: Ethyl 3-(4-(difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. (E)-Ethyl 3-(4-(difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (500 mg, 1.78 mmol), (3-(hydroxymethyl)-4-methylphenyl)boronic acid (885 mg, 5.33 mmol), and aq. KOH (1.8 mL, 1 M, 1.8 mmol) were added to a sealed tube and the resulting mixture dissolved in 1,4-dioxane (15 mL). The mixture was sparged with Ar for 20 minutes and then treated with [Rh(cod)Cl]₂ (88 mg, 0.18 mmol). The mixture was sparged with Ar for another 20 minutes. The resultant mixture was stirred at room-temperature for 16 hours under Ar. The suspension was filtered and the filtrate concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 0:1, dichloromethane/methanol, 20:1, isocratic) to afford the title compound (378.7 mg, 52%). MS (ESI): mass calcd. for C₂₁H₂₃F₂N₃O₃ 403.17 m/z, found 404.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.75 (m, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.33-7.30 (m, 1H), 7.19-7.12 (m, 1H), 7.06 (d, J=8.0 Hz, 1H), 5.14 (t, J=7.8 Hz, 1H), 5.01 (t, J=5.3 Hz, 1H), 4.46-4.36 (m, 2H), 4.30 (s, 3H), 3.99-3.90 (m, 2H), 3.30-3.21 (m, 1H), 3.15-3.06 (m, 1H), 2.16 (s, 3H), 1.04 (t, J=7.2 Hz, 3H).

Intermediate 61: 5′-methyl-2′,3′-dihydro-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepine] 1′,1′-dioxide

Step A: tert-Butyl (1-carbamoylcyclopropyl)carbamate. Pyridine (11.8 g, 149 mmol) was added drop-wise to a mixture of 1-((tertbutoxycarbonyl)amino)cyclopropanecarboxylic acid (50.0 g, 248 mmol), Boc₂O (70.5 g, 323 mmol), NH₄HCO₃ (24.6 g, 311 mmol), and MeCN (500 mL) over a period of 10 minutes. The mixture was stirred at room temperature for 16 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (100 mL), pH adjusted to 7 with 1 N HCl, and then the resultant mixture extracted with ethyl acetate(3×). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (40.1 g, 80%), which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 6.42 (br s, 1H), 5.71 (br s, 1H), 5.18 (br s, 1H), 1.61-1.56 (m, 2H), 1.46-1.45 (m, 9H), 1.09-0.98 (m, 2H).

Step B: tert-Butyl (1-cyanocyclopropyl)carbamate. TFAA (47.3 g, 225 mmol) was added drop-wise to solution of tert-butyl (1-carbamoylcyclopropyl)carbamate (30.0 g, 150 mmol), triethylamine (62.7 g, 450 mmol), and dichloromethane (180 mL) over a period of 1 hour. The resultant mixture was stirred at room-temperature for 4 hours before concentrating to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate, 1:0 to 5:1, gradient elution) to afford the title compound (22.5 g, 82.3%). ¹H NMR (400 MHz, CDCl₃) δ 6.60 (br s, 1H), 2.63 (s, 9H), 1.28 (s, 2H), 1.24-1.20 (m, 1H), 1.07-1.01 (m, 1H).

Step C: tert-Butyl (1-cyanocyclopropyl)(methyl)carbamate. Sodium hydride in mineral oil (15.0 g, 60% purity, 375 mmol) was added in portions to a 0° C. (ice/water) solution of tert-butyl (1-cyanocyclopropyl)carbamate (22.5 g, 123 mmol) and THF (150 mL). The resultant mixture was treated with iodomethane (34.7 g, 244 mmol) by drop-wise addition at 0° C. and then stirred for 12 hours with gradual warming to room-temperature before quenching with sat. NH₄Cl (100 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions which were combined, washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (23.0 g), which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 2.90 (s, 3H), 1.48 (s, 9H), 1.27-1.26 (m, 2H), 0.86-0.82 (m, 2H).

Step D: tert-Butyl (1-(aminomethyl)cyclopropyl)(methyl)carbamate. Raney Ni (2 g) was added to a 1 L round-bottomed flask containing a mixture of tert-butyl (1-cyanocyclopropyl)(methyl)carbamate (23 g), methanol (200 mL), and 25% aqueous NH₃(aq) (5 mL) under Ar. The resultant mixture was stirred under H₂ (15 psi) at room-temperature for 15 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to afford the title product (25 g), which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 2.86 (br s, 3H), 1.84-1.80 (m, 2H), 1.44 (br s, 9H), 1.23-1.22 (m, 2H), 0.85-0.81 (m, 2H).

Step E: tert-Butyl (1-((2-chloropyridine-3-sulfonamido)methyl)cyclopropyl)(methyl)carbamate. A solution of 2-chloropyridine-3-sulfonyl chloride (20 g, 94 mmol) and THF (50 mL) was added drop-wise to a 0° C. mixture of tert-butyl (1-(aminomethyl)cyclopropyl)(methyl)carbamate (20 g), K₂CO₃ (20.0 g, 145 mmol), THF (150 mL), and H₂O (40 mL). The mixture was stirred for 12 hours with gradual warming to room-temperature before concentrating to dryness under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (30 g), which was used in the next step without purification. MS (ESI): mass calcd. for C₁₅H₂₂ClN₃O₄S 375.1 m/z, found 398.0 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.58-8.54 (m, 1H), 8.40-8.35 (m, 1H), 7.45-7.36 (m, 1H), 6.83 (br s, 1H), 3.07-2.98 (m, 2H), 2.82 (s, 3H), 1.47 (s, 9H), 0.97-0.93 (m, 2H), 0.85-0.78 (m, 2H).

Step F: 2-Chloro-N-((1-(methylamino)cyclopropyl)methyl)pyridine-3-sulfonamide. TFA (30.0 mL, 433 mmol) was added to a 0° C. solution of tert-butyl (1-((2-chloropyridine-3-sulfonamido)methyl)cyclopropyl)(methyl)carbamate (35 g) and dichloromethane (100 mL). The mixture was stirred for 2 hours with gradual warming to room-temperature before concentrating to dryness under reduced pressure to afford the title compound (30 g), which was used in the next step without further purification. MS (ESI): calcd. for C₁₀H₁₄ClN₃O₂S 275.1, m/z found 275.9 [M+H]⁺.

Step G: 5′-Methyl-3′,5′-dihydro-2′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepine] 1′,1′-dioxide. DIPEA (30.0 mL, 172 mmol) was added drop-wise to a solution of 2-chloro-N-((1-(methylamino)cyclopropyl)methyl)pyridine-3-sulfonamide (10 g) and DMSO (60 mL). The resultant mixture was stirred while heating at 160° C. for 2 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with H₂O (200 mL) and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was triturated with ethyl acetate: petroleum ether (1:10, 80 mL). The suspension was isolated via filtration and the filter cake washed with ethyl acetate:petroleum ether (1:30, 30 mL) before drying under reduced pressure to afford the title compound (3.58 g, 41%). MS (ESI): mass calcd. For C₁₀H₁₃N₃O₂S 239.1 m/z, found 240.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.19 (m, 1H), 8.15-7.79 (m, 2H), 6.98-6.89 (m, 1H), 3.32-3.06 (m, 2H), 3.02 (s, 3H), 0.99-0.57 (m, 4H).

Intermediate 62: (2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

(5-Bromo-2-chlorophenyl)methanol (15.0 g, 67.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (27.5 g, 108 mmol), KOAc (19.9 g, 203 mmol), and 1,4-dioxane (100 mL) were added to a 250 mL round-bottomed flask under N₂. The mixture was sparged with N₂ for 5 minutes and then treated with Pd(dppf)Cl₂.CH₂Cl₂ (4.96 g, 6.07 mmol). The mixture was sparged with N₂ for another 5 minutes and then stirred at 100° C. for 16 hours before cooling to room-temperature. The resultant mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to afford the product, which was purified by preparative HPLC (eluent: CH₃CN/H₂O and H₂O with 0.04% NH₃, 1:5 to 1:1, gradient elution) to afford pure product. The product was suspended in water (10 mL), the mixture frozen using dry ice/acetone, and then lyophilized to dryness to afford the title product (6.8 g) as a white solid.

The white solid (6.8 g) was further purified by FCC (eluent: petroleum ether/ethyl acetate, 20:1 to 0:1) to afford the title compound (4.0 g, 22%). MS (ESI): mass calcd. for C₁₃H₁₈BClO₃ 268.1 m/z, found 251.0 [M−H₂O+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.68-7.63 (m, 1H), 7.35 (d, J=7.9 Hz, 1H), 4.77 (d, J=6.4 Hz, 2H), 1.90 (t, J=6.6 Hz, 1H), 1.33 (s, 12H).

Intermediate 63: (S*)-3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: 2-Chloro-5-methylpyridine-3-sulfonyl chloride. HBF₄ (7.6 mL, 48 mmol) was added drop-wise to a 100 mL three-necked round-bottomed flask containing a 0° C. solution of 2-chloro-5-methylpyridin-3-amine (5.0 g, 35 mmol) and acetonitrile (30 mL). The resultant mixture was stirred at 0° C. for 10 minutes before adding tert-Butyl nitrite (6.3 mL, 53 mmol) drop-wise at 0° C. The resultant mixture was stirred at 0° C. for another 1 hour. Copper(I) chloride (5.5 g, 56 mmol) and acetic acid (50 mL) were added to a 250 mL three-necked round-bottomed flask. The resultant mixture was cooled to 0° C., bubbled with SO₂ gas (>1.3 M) at 0° C. for 1 hour, and then treated with the above 2-chloro-5-methylpyridine-3-diazonium tetrafluoroborate solution by drop-wise addition at 0° C. The resultant mixture was stirred for 4 hours with gradual warming to room-temperature before quenching with sat. NaHCO₃(100 mL). The resultant mixture was stirred for 20 minutes and then extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, washed with water (2×), dried over sodium sulfate and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate, 1:0 to 10:1, gradient elution) to afford the title compound (3 g, 38%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.27-8.19 (m, 1H), 2.46 (s, 3H).

Step B: tert-Butyl 2-((2-chloro-5-methylpyridine-3-sulfonamido)methyl)piperidine-1-carboxylate. A solution consisting of 2-chloro-5-methylpyridine-3-sulfonyl chloride (2.5 g, 11 mmol) and THF (10 mL) was added drop-wise to a 0° C. mixture of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (2.5 g, 12 mmol), K₂CO₃ (2.5 g, 18 mmol), THF (10 mL), and H₂O (5 mL). The resultant mixture was stirred for 2 hours with gradual warming to room-temperature before concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) and the resultant mixture extracted with ethyl acetate (2×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (3.5 g, 77%). MS (ESI): mass calcd. for C₁₇H₂₆ClN₃O₄S 403.1, found 426.0 [M+Na]⁺.

Step C: 2-Chloro-5-methyl-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide. TFA (5.0 mL, 72 mmol) was added to a 0° C. solution consisting of tert-butyl 2-((2-chloro-5-methylpyridine-3-sulfonamido)methyl)piperidine-1-carboxylate (3.5 g, 8.7 mmol) and dichloromethane (20 mL). The resultant mixture was stirred for 12 hours with gradual warming to room-temperature before concentrated to dryness under reduced pressure to afford the title compound (3.1 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₂H₁₈ClN₃O₂S 303.1, found 303.9 [M+H]⁺.

Step D: 3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. DIPEA (8.0 mL, 46 mmol) was added drop-wise to a solution of 2-chloro-5-methyl-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide (3.0 g) and DMSO (20 mL). The resultant mixture was stirred and heated at 160° C. for 2 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (200 mL), and the resultant mixture extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate, 1:0 to 3:1, gradient elution) to afford the title compound (1.6 g). MS (ESI): mass calcd. for C₁₂H₁₇N₃O₂S 267.1, m/z found 267.9 [M+H]⁺.

Step E: (S*)-3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. The mixture of 3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (1.6 g, 6.0 mmol) isomers were separated by purified by chiral SFC (stationary phase: AD 250 mm×50 mm, mobile phase: 40% CO₂, 40% EtOH and H₂O with 0.1% NH₃) to afford two diastereomers. The first eluting isomer (370 mg) was designated *S: ¹H NMR (400 MHz, DMSO-d₆) δ 8.11-8.07 (m, 1H), 8.05-7.99 (m, 1H), 7.72-7.66 (m, 1H), 4.19-4.06 (m, 2H), 3.47-3.38 (m, 1H), 3.32-3.24 (m, 1H), 3.19-3.10 (m, 1H), 2.18 (s, 3H), 1.72-1.49 (m, 6H).

Intermediate 64: (S*)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: 2-Chloro-5-fluoropyridin-3-amine. Fe (15.2 g, 272 mmol) was added in portions to a solution of 2-chloro-5-fluoro-3-nitropyridine (12 g, 68 mmol) and HOAc (200 mL). The reaction mixture was stirred at 80° C. for 0.5 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was suspended in ethyl acetate (100 mL), the resultant suspension filtered through a pad of Celite®, and the pad washed with ethyl acetate (20 mL). The filtrate was neutralized with sat. NaHCO₃(200 mL) and the resultant mixture extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to give the product (11 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₅H₄ClFN₂ 146.0, found 146.8 [M+H]⁺.

Step B: 2-Chloro-5-fluoropyridine-3-sulfonyl chloride. HBF₄ (59.2 mL, 380 mmol) was added drop-wise to a 1 L three-necked round-bottomed flask containing a 0° C. mixture of 2-chloro-5-fluoropyridin-3-amine (40.0 g, 273 mmol) and acetonitrile (300 mL). The resultant mixture was stirred at 0° C. for 10 minutes before drop-wise addition of tert-butyl nitrite (48.8 mL, 410 mmol) at 0° C. The resultant mixture was stirred at 0° C. for another 1 hour. Copper(I) chloride (30.3 g, 303 mmol) and acetic acid (100 mL) were added to a 1 L three-necked round-bottomed flask. The resultant mixture was cooled to 0° C., bubbled with SO₂ gas (>1.3 M) at 0° C. for 1 hour followed by drop-wise addition of the 2-chloro-5-fluoropyridine-3-diazonium tetrafluoroborate solution at 0° C. The resultant mixture was stirred for 4 hours with gradual warming to room-temperature before quenching with sat. NaHCO₃(100 mL). The resultant mixture was stirred for 20 minutes and then extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the product which was purified by FCC (eluent: petroleum ether/ethyl acetate, 1:0 to 9:1, gradient) to afford the title compound (30 g).

Step C: tert-Butyl 2-((2-chloro-5-fluoropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate. A solution consisting of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (30.7 g, 143 mmol) and THF (100 mL) was added drop-wise to a 0° C. mixture consisting of 2-chloro-5-fluoropyridine-3-sulfonyl chloride (30 g), K₂CO₃ (28.8 g, 208 mmol), THF (100 mL), and H₂O (40 mL). The resultant mixture was stirred for 2 hours with gradual warming to room-temperature before concentrating to dryness under reduced pressure. The residue was diluted with water (80 mL) and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate, 1:0 to 5:1, gradient) to afford the title compound (35 g, 64%). MS (ESI): mass calcd. for C₁₆H₂₃ClFN₃O₄S 407.1, found 308.1 [M+H-Boc]⁺.

Step D: 2-Chloro-5-fluoro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide. TFA (40 mL) was added to a solution of tert-butyl 2-((2-chloro-5-fluoropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate (23.0 g, 56.4 mmol) and dichloromethane (80 mL). The resultant mixture was stirred at room temperature for 3 hours before concentrating to dryness under reduced pressure to afford the title product (17 g), which was used in the next step without purification. MS (ESI): mass calcd. for C₁₁H₁₅ClFN₃O₂S 307.1, found 308.0 [M+H]⁺.

Step E: 3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. DIPEA (50.0 mL, 287 mmol) was added drop-wise to a solution of 2-chloro-5-fluoro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide (17 g) and DMSO (150 mL) at room temperature. The resultant mixture was stirred at 160° C. for 2 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (200 mL), and the resultant mixture extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate, 1:0 to 3:1, gradient) to afford the title compound (11 g). MS (ESI): mass calcd. for C₁₁H₁₄FN₃O₂S 271.1, m/z found 271.9 [M+H]⁺.

Step F: (*S)-3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. The mixture of 3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (11 g, 40 mmol) isomers were separated by purified by chiral SFC (AS 250 mm×50 mm, mobile phase: 30% CO₂, 30% EtOH and H₂O with 0.1% NH₃) to afford two diastereomers. The first eluting isomer (5.2 g) was designated *S. MS (ESI): mass calcd. for C₁₁H₁₄FN₃O₂S 271.1, m/z found 272.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=3.2 Hz, 1H), 8.22 (br s, 1H), 7.86-7.74 (m, 1H), 4.20-4.08 (m, 2H), 3.47 (t, J=12.8 Hz, 1H), 3.30-3.22 (m, 1H), 3.21-3.11 (m, 1H), 1.71-1.48 (m, 6H).

Intermediate 65: 8-fluoro-2,3-dihydrospiro[benzo][b][1,4,5]oxathiazepine-4,1′-cyclopropane] 1′,1′-dioxide

Step A: 2,5-difluoro-N-((1-hydroxycyclopropyl)methyl)benzenesulfonamide. In a 250 mL round bottom flask was added 1-(aminomethyl))cyclopropanol (3.1 g, 35 mmol), THF (90 mL) and water (21 mL). To this mixture was added potassium carbonate (3.9 g, 28 mmol) and 2,5-difluorobenzenesulfonyl chloride (5.0 g, 23 mmol). After stirring at r.t. for 18 h. the mixture was partitioned between ethyl acetate/water and the aqueous layer extracted once more with ethyl acetate. These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexanes, 0:1 to 1:0, gradient elution) providing the title product. MS (ESI): mass calcd. for C₁₀H₁₁F₂NO₃S 263.0, m/z found 264.0 [M+H]⁺.

Step B: 8-fluoro-2,3-dihydrospiro[benzo][b][1,4,5]oxathiazepine-4,1′-cyclopropane] 1′,1′-dioxide. To a 100 mL round bottom flask was added 2,5-difluoro-N-((1-hydroxycyclopropyl)methyl)benzenesulfonamide (938 mg, 3.6 mmol), potassium carbonate (3.5 mL, 10.5 mmol, 3M solution in water), and DMSO (15 mL). The reaction was heated to 90° C. and allowed to stir for 20 h. The reaction was cooled, volume reduced to about half, poured into water and extracted with ethyl acetate (5×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexanes, 0:1 to 1:0, gradient elution) to afford the title compound (365 mg, 42%). MS (ESI): mass calcd. for C₁₀H₁₀FNO₃S 243.0, m/z found 243.9 [M+H]⁺.

Intermediate 66: 8-fluoro-2,3-dihydrospiro[benzo][b][1,4,5]oxathiazepine-4,3′-oxetane] 1′,1′-dioxide

The title compound (820 mg, 34%) was prepared using analogous conditions as described in Intermediate 65 where 3-(aminomethyl)oxetan-3-ol was used instead of 1-(aminomethyl))cyclopropanol in step A. MS (ESI): mass calcd. for C₁₀H₁₀FNO₄S 259.0, m/z found 260.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (dd, J=7.4, 3.0 Hz, 1H), 7.34 (dd, J=8.8, 4.3 Hz, 1H), 7.25-7.20 (m, 1H), 5.08 (s, 1H), 4.67 (d, J=7.5 Hz, 2H), 4.38-4.27 (m, 2H), 3.95 (d, J=5.7 Hz, 2H).

Intermediate 67: 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2,6-dichloropyridine-3-sulfonyl chloride. SOCl₂ (365 g, 3.07 mol) was added dropwise to H₂O (1.6 L) chilled to 0-5° C. and allowed to stir at 0-15° C. for 16 h. To a second flask was added 2,6-dichloropyridin-3-amine (100 g, 613 mmol) and HCl (745 g, 7.36 mol, 36% purity). To this mixture was added a solution of NaNO₂ (50.8 g, 736 mmol) in H₂O (160 mL) at 0° C. After addition, the orange suspension was stirred at 0° C. for 0.5 h. CuCl (6.07 g, 61.3 mmol) was added to the first flask followed by immediate drop-wise addition of the suspension from the second flask at 0-5° C. The suspension was stirred at 0-5° C. for 1 h. The suspension was extracted with EtOAc (3×). These extractions resulted in several fractions which were washed with brine (2×), combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was stirred in petroleum ether (300 mL) for 1 hr. The mixture was filtered, and the cake was washed with petroleum ether (50 mL). The cake was dried in vacuum to give the desired product (94.1 g, 48% yield). MS (ESI): mass calcd. for C₅H₂Cl₃NO₂S 244.9, m/z found 297.1. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H).

Step B: 2,6-dichloro-N-((1-hydroxycyclopropyl)methyl)pyridine-3-sulfonamide. To a mixture of 1-(aminomethyl)cyclopropane-1-ol (18.5 g, 212 mmol) and K₂CO₃ (42.0 g, 304.2 mmol) in THF (500 mL) and H₂O (150 mL) was added 2,6-dichloropyridine-3-sulfonyl chloride (50.0 g, 202 mmol) in THF (150 mL) drop-wise while keeping the reaction temperature between 0-5° C. The reaction mixture was stirred at 20° C. for 16 hrs. followed by extraction of the suspension with EtOAc (3×). These extractions resulted in several fractions which were combined, washed with water (1×), brine (1×), dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, 0:1 to 1:3, gradient elution) to afford the title compound (63.1 g, 86.9%). MS (ESI): mass calcd. for C₉H₁₀Cl₂N₂O₃S 296.0, m/z found 296.9 [M+H]⁺.

Step C: 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. To a solution of 2,6-dichloro-N-((1-hydroxycyclopropyl)methyl)pyridine-3-sulfonamide (61.3 g, 173 mmol) in DMSO (1.2 L) was added K₂CO₃ (71.8 g, 519 mmol). The yellow suspension was stirred at 60° C. for 4 hrs. The suspension was poured into water (3 L), and extracted with EtOAc (3×). These extractions resulted in several fractions which were combined, washed with water (2×) and brine (1×), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluent: MeCN/water (0.1% TFA), 1:9 to 2:3, gradient elution) to afford the title compound (18.5 g, 40.0%). MS (ESI): mass calcd. for C₉H₁₉ClN₂O₃S 260.0, m/z found 261.0 [M+H]⁺.

Intermediate 68: 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 4-hydroxytetrahydro-2H-4-carbonitrile. To a solution of tetrahydro-4H-4-one (50.0 g, 499 mmol) in THF (1.5 L) was added TMSCN (49.5 g, 499 mmol) followed by BF₃.Et₂O (74.4 g, 524 mmol). The internal temperature of the reaction was maintained below 10° C. during the addition of the BF₃.Et₂O. The reaction mixture was stirred at 20° C. for 3 hrs. The reaction mixture was diluted with sat. aq. NaHCO₃(1.5 L) and extracted with EtOAc (3×). These extractions resulted in several fractions which were combined, washed with brine (1×), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, 0:1 to 3:7, gradient elution) to afford the title compound (56.4 g, 88.8%).

Step B: 4-(aminomethyl)tetrahydro-2H-pyran-4-ol. To a solution of LAH (19.0 g, 487 mmol) in THF (500 mL) at 0° C. under N₂ was added dropwise 4-hydroxytetrahydropyran-4-carbonitrile (56.4 g, 443 mmol) in THF (100 mL). The reaction was allowed to warm to 20° C. followed by addition of H₂O (19 mL), 15% NaOH (19 mL) and H₂O (19 mL). The reaction was filtered and concentrated under reduced pressure to give the title compound (43.6 g, 74.9%), which was used directly in the next step without purification.

Step C. 2,6-dichloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide. To a mixture of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (30.0 g, 229 mmol) and K₂CO₃ (45.2 g, 327 mmol) in THF (300 mL) and H₂O (90 mL) was added drop-wise 2,6-dichloropyridine-3-sulfonyl chloride (63.1 g, 217 mmol) in THF (90 mL) keeping the inner temperature between 0° C. and 5° C. The reaction mixture was then stirred at 15° C. for 13 hrs.

The suspension was poured into water (200 mL) and extracted with EtOAc (3×). These extractions resulted in several fractions which were combined, washed with brine (1×), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, 0:1 to 3:7, gradient elution) to afford the title compound (45.4 g, 58.0%). MS (ESI): mass calcd. for C₁₁H₁₄Cl₂N₂O₄S 340.0, m/z found 341.1 [M+H]⁺.

Step D: 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. To a solution of 2,6-dichloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide (14.6 g, 42.8 mmol) in THF (300 mL) was added t-BuOK (4.80 g, 42.8 mmol). The mixture was stirred at 10° C. for 1.5 hrs. The suspension was poured into water (50 mL), extracted with EtOAc (5×). These extractions resulted in several fractions which were combined, washed with brine (IX), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure washed. The residue was stirred in 30 mL mixture of petroleum ether:ethyl acetate (3:1, 50 mL) for 30 min. The mixture was filtered off and the cake was washed with petroleum ether and ethyl acetate (5:1, 20 mL) and dried under vacuum to give the title compound (10.7 g, 48.4%). MS (ESI): mass calcd. for C₁₁H₁₃ClN₂O₄S 304.0, m/z found 304.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.55 (s, 1H) 8.17 (d, J=8.0, 1H) 7.5 (d, J=8.0 Hz, 1H) 3.75 (m, 2H) 3.62 (d, J=11.3 Hz, 2H) 3.53 (s, 2H) 1.64 (m, 4H)

Intermediate 69: Methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiropyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

The title compound (760 mg, 73%) was prepared using analogous conditions as described in Example 11 where methyl 3-(3-(hydroxy methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 48) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 68) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₃H₃₅ClF₃N₅O₆S, 721.2; m/z found, 722.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.17-7.10 (m, 2H), 7.03 (d, J=1.2 Hz, 2H), 4.72 (s, 1H), 4.47-4.33 (m, 2H), 3.98-3.90 (m, 2H), 3.60-3.45 (m, 6H), 3.38-3.32 (m, 1H), 2.71 (s, 3H), 2.16 (s, 3H), 1.71-1.57 (m, 2H), 1.49-1.37 (m, 2H), 1.35 (s, 3H), 1.29 (s, 3H).

Intermediate 71: Benzyl (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

Step A: (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. To a solution of methyl (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 145, 2.64 g, 5.9 mmol) in a 1:1 mixture of methanol (24 mL) and THF (24 mL) was added a 1M solution of LiOH in water (42 mL). The mixture was heated at 60° C. for 18 h, cooled, and the pH adjusted to ˜5 with 1M HCl. The resulting precipitate was collected and washed with water. The aqueous filtrate was extracted with ethyl acetate (4×) resulting in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The precipitate and the residue from extraction were combined to afford the title compound (2.48 g, 99%). MS (ESI): mass calcd. for C₁₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.43 (d, J=7.3 Hz, 1H), 7.35-7.25 (m, 2H), 7.15 (dd, J=7.9, 2.1 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 5.02 (s, 1H), 4.79 (s, 1H), 4.43 (s, 2H), 2.67 (s, 3H), 2.18 (s, 3H), 1.32-1.24 (m, 6H).

Step B: benzyl (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a flask under N₂ was added (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (500 mg, 1.19 mmol), potassium carbonate (410 mg, 2.97 mmol) and acetonitrile (5.0 mL). After stirring for 5 minutes, benzyl bromide (0.17 mL, 1.43 mmol) was added to the mixture followed by stirring at r.t. for an additional 24 h. The reaction was poured into water and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexanes, 0:1 to 1:0, gradient elution) to afford the title compound (540 mg, 89%). MS (ESI): mass calcd. for C₂₄H₂₈F₃N₃O₃, 511.2; m/z found, 512.3 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.25 (d, J=7.2 Hz, 1H), 7.28-7.22 (m, 2H), 7.10-7.00 (m, 7H), 5.09-5.00 (m, 2H), 4.87 (d, J=12.1 Hz, 1H), 4.71 (s, 1H), 4.41 (d, J=5.4 Hz, 2H), 2.54 (s, 3H), 2.16 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H).

Intermediate 72: 8′-Methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

Step A: 6-Bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methylpyridine-3-sulfonamide. A solution of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (14.0 g, 83.5 mmol) in THF:H₂O (230 mL, 4:1) was cooled to 0° C. and K₂CO₃ (26.2 g, 189 mmol) was added in portions to it. The resultant mixture was stirred for 5 min at 0° C. and then treated with 6-bromo-2-chloro-5-methylpyridine-3-sulfonyl chloride (23.1 g, 75.7 mmol). This mixture was stirred at room-temperature for 12 hours before pouring it into water (80 mL) and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions which were combined, washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (27.8 g). MS (ESI): mass calcd. for C₁₂H₁₆BrClN₂O₄S 399.7 m/z found 400.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (m, 1H), 8.05 (m, 1H), 4.39 (s, 1H), 3.57-3.51 (m, 4H), 2.89 (d, J=5.1 Hz, 2H), 2.40 (s, 3H), 1.55-1.45 (m, 2H), 1.33 (d, J=13.0 Hz, 2H).

Step B: 7′-Bromo-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. t-BuOK (7.91 g, 70.5 mmol) was added in portions to a solution of 6-bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide (14.1 g, 35.2 mmol) and DMSO (110 mL) at 0° C. The resultant mixture was stirred at 100° C. for 2 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with H₂O (60 mL), the mixture acidified with 1 N HCl (100 mL) to pH=6, and the suspension isolated via filtration. The filter cake was washed with petroleum ether (60 mL) before drying under reduced pressure to give the product (10.08 g, 79%). The product (8.28 g) was purified by preparative HPLC (stationary phase: YMC Triart C18, 250 mm×50 mm×7 μm column; eluent: 10% to 40% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to afford the title compound (7.13 g, 56%). MS (ESI): mass calcd. for C₁₂H₁₅BrN₂O₄S 363.2 m/z found 363.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (m, 1H), 8.09 (m, 1H), 3.79-3.70 (m, 2H), 3.61 (d, J=11.2 Hz, 2H), 3.50 (s, 2H), 2.36 (s, 3H), 1.69-1.55 (m, 4H).

Step C: 8′-Methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. Cs₂CO₃ (6.72 g, 20.6 mmol) was added to a mixture of 7′-bromo-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (2.5 g, 6.9 mmol), 2-(pyrrolidin-1-yl)ethanol (2.67 g, 20.7 mmol), JosiPhos pre-catalyst G3 (0.64 g, 0.70 mmol), and DMA (30 mL) under Na. The resultant mixture was stirred at 95° C. for 16 hours before quenching with H₂O and extracting with ethyl acetate (2×). These extractions resulted in several fractions which were combined dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 0:1, gradient) to afford the title compound (2.1 g, 69.5%). MS (ESI): mass calcd. for C₁₉H₂₉N₃O₅S 411.5 m/z found 412.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (m, 1H), 7.83 (m, 1H), 4.39 (t, J=6.1 Hz, 2H), 3.87-3.76 (m, 2H), 3.62 (d, J=11.0 Hz, 2H), 3.43 (s, 2H), 2.66 (t, J=6.1 Hz, 2H), 2.44 (s, 4H), 2.12 (s, 3H), 1.60 (s, 4H), 1.51-1.45 (m, 4H), 1.40-1.33 (m, 2H).

Intermediate 73: 7′-(2-(Piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

To a solution of 2-piperidin-1-yl)ethan-1-ol (2.00 mL, 14.9 mmol) in DMSO (20 mL), which had been cooled to 0° C., was added NaH (558 mg, 13.9 mmol). The mixture was stirred at 0° C. for 2 minutes then allowed to warm to room temperature and stirred for an additional 45 minutes. 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (1.00 g, 3.28 mmol, Intermediate 68) was then added as a solid in one portion and the reaction was stirred for an additional 15 h. The reaction was then quenched with saturated NH₄Cl and the pH adjusted to about 7 with 1M aqueous HCl solution. The aqueous layer was extracted with ethyl acetate (5×) resulting in several organic fractions that were combined, washed with brine (IX), dried over MgSO₄ and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate/methanol; 1:0 to 9:1, gradient elution) to afford the title compound (1.00 g, 77%). MS (ESI): mass calcd. for C₁₈H₂₇N₃O₅S 397.2 m/z found 398.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.38 (t, J=6.0 Hz, 2H), 3.85-3.78 (m, 2H), 3.67-3.60 (m, 2H), 3.47 (s, 2H), 2.65 (t, J=6.0 Hz, 2H), 2.45-2.38 (m, 4H), 1.69-1.58 (m, 4H), 1.52-1.45 (m, 4H), 1.41-1.33 (m, 2H).

Intermediate 74: (*R)-Methyl 3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: (E)-tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)acrylate. tert-Butyl acrylate (477 mg, 3.72 mmol), Pd(OAc)₂ (32.1 mg, 0.143 mmol), 2-(di-tert-butylphosphino)biphenyl (85.5 mg, 0.287 mmol), and Et₃N (580 mg, 5.73 mmol) were added to a solution of 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (1.00 g, 2.86 mmol) and DMF (18 mL). The resultant mixture was sparged with N₂ for 5 minutes and then stirred while heating at 120° C. for 3 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with sat. NH₄Cl (7 mL) and the resultant mixture was extracted with ethyl acetate (2×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:5, gradient elution) to afford the title compound (805 mg, 71%). MS (ESI): mass calcd. for C₁₈H₂₄N₂O₆S 396.1 m/z found 396.9 [M+H]⁺.

Step B: tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate. (E)-tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)acrylate (805 mg, 2.03 mmol), MeOH (10 mL), and dry Pd/C (200 mg, 10 wt. %, 0.189 mmol) were added to a 75 mL hydrogenation bottle. The resultant mixture was stirred at room-temperature for 16 hours under H₂ (50 psi). The suspension was filtered through a pad of diatomaceous earth and the pad washed with MeOH (20 mL). The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:5, gradient elution) to afford the title compound (780.5 mg). MS (ESI): mass calcd. for C₁₈H₂₆N₂O₆S 398.1 m/z found 399.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60-8.10 (m, 1H), 8.02 (d, J=7.83 Hz, 1H), 7.24 (d, J=7.83 Hz, 1H), 3.81 (t, J=9.78 Hz, 2H), 3.57 (d, J=10.76 Hz, 2H), 3.47 (s, 2H), 2.97 (t, J=6.97 Hz, 2H), 2.64 (t, J=6.97 Hz, 2H), 1.72-1.46 (m, 4H), 1.34 (s, 9H).

Step C: (*R)-Methyl 3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DIAD (2.33 g, 11.5 mmol) was added to a solution of (*R)-methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 141, 2.5 g, 5.7 mmol), tert-butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate (2.75 g, 6.90 mmol), PPh₃ (3.02 g, 11.5 mmol), and THF (30 mL). The resultant mixture was stirred at room temperature for 3 hours before concentrating to dryness under reduced pressure to give the product, which was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:3, gradient elution) to afford the title compound (6.1 g, 47%). MS (ESI): mass calcd. for C₄₀H₄₈F₃N₅O₈S 815.32 m/z found 816.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.09 Hz, 1H), 8.05 (d, J=7.83 Hz, 1H), 7.29 (d, J=7.83 Hz, 1H), 7.25-7.16 (m, H), 7.16-7.09 (m, 1H), 4.80 (s, 1H), 4.54-4.24 (m, 2H), 3.76 (d, J=9.05 Hz, 2H), 3.55-3.40 (m, 6H), 2.99 (t, J=6.85 Hz, 2H), 2.76-2.59 (m, 5H), 2.15 (s, 3H), 2.07 (s, 1H), 1.52-1.40 (m, 4H), 1.36 (s, 12H), 1.29 (s, 3H).

Intermediate 75: (S)-6,7,7a,8,9,10-Hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

The title compound (4.3 g) was prepared using analogous conditions as described in Intermediate 4 using tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate instead of tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate in Step A. MS (ESI): mass calcd. for C₁₀H₁₃N₃O₂S, 239.1; m/z found, 240.1 [M+H]⁺.

Intermediate 76: (*S)-7,7a,8,9,10,11-Hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl 24(2-fluorophenyl)sulfonamido)methyl)piperidine-1-carboxylate. 2-Fluorobenzene-1-sulfonyl chloride (15 g, 77 mmol) was added in portions to a mixture of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (17 g, 81 mmol) and potassium carbonate (13 g, 93 mmol) in THF (150 mL) and water (38 mL). After 16 hours, sodium sulfate was added and the suspension was filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound as a yellow oil (28 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dt, J=7.5, 1.8 Hz, 1H), 7.61-7.53 (m, 1H), 7.30-7.25 (m, 1H), 7.21 (t, J=9.5 Hz, 1H), 5.14 (br s, 1H), 4.33 (br s, 1H), 3.88 (br d, J=12.6 Hz, 1H), 3.34 (br s, 1H), 2.59 (br s, 1H), 1.69-1.52 (m, 5H), 1.47 (s, 9H), 1.41-1.33 (m, 2H).

Step B: 2-Fluoro-N-(piperidin-2-ylmethyl)benzenesulfonamide hydrochloride. tert-Butyl 2-(((2-fluorophenyl)sulfonamido)methyl)piperidine-1-carboxylate (24 g, 64 mmol) was dissolved in a mixture of 4 M HCl in methanol (81 mL, 320 mmol). After 2 hours, the mixture was concentrated to dryness under reduced pressure to afford the title compound as a white solid which was used in the next step without further purification (19.9 g). ¹H NMR (400 MHz, DMSO-d₆) δ 9.26-9.05 (m, 2H), 8.38 (br t, J=5.7 Hz, 1H), 7.82 (dt, J=7.6, 1.5 Hz, 1H), 7.77-7.70 (m, 1H), 7.51-7.38 (m, 2H), 3.24-3.16 (m, 2H), 3.10-2.98 (m, 2H), 2.87-2.73 (m, 1H), 1.88-1.56 (m, 4H), 1.40 (br s, 2H).

Step C: (*S)-7,7a,8,9,10,11-Hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. The below reaction was run three times on 2 different scale: twice using 5 g of 2-fluoro-N-(piperidin-2-ylmethyl)benzenesulfonamide hydrochloride and once using 13.2 g. The 13.2 g scale reaction details are provided. A solution containing 2-fluoro-N-(piperidin-2-ylmethyl)benzenesulfonamide hydrochloride (13.2 g, 42.7 mmol), DIPEA (27.6 g, 214 mmol) and DMSO (240 mL) was degassed by bubbling nitrogen through the solution for 5 minutes. The mixture was warmed to 160° C. After 6 hours, the solution was cooled to room temperature. At this point, the cooled reaction mixture was combined with the two additional reaction mixtures referred to above for further processing. The combined mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organics extracts were dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (4:1, 40 mL) to afford a suspension. The solids were isolated by filtration and then dried to provide the title compound as a mixture of enantiomers (5.73 g). The mixture of isomers was separated by chiral SFC (stationary phase: Chiralcel OD-H 5 μm 3×25 cm; mobile phase: 25% methanol, 75% CO₂ with 0.3% iPrNH₂) to afford two enantiomers. The first eluting isomer (2.16 g) was designated (*S): ¹H NMR (400 MHz, DMSO-d₆) δ 7.79-7.69 (m, 1H), 7.61-7.56 (m, 1H), 7.42-7.35 (m, 1H), 7.19-7.14 (m, 1H), 7.03-6.96 (m, 1H), 3.73 (s, 1H), 3.52-3.33 (m, 3H), 3.10-2.98 (m, 1H), 1.74-1.51 (m, 6H).

Intermediate 77: (*S)-3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: 2-Chloro-5-methylpyridine-3-sulfonyl chloride. HBF₄ (7.6 mL, 48 mmol) was added dropwise to a solution of 2-chloro-5-methylpyridin-3-amine (5.0 g, 35 mmol) in acetonitrile (30 mL) at 0° C. After 10 minutes, tert-butyl nitrite (6.3 mL, 53 mmol) was added dropwise. After 1 hour, this solution was added to mixture of copper chloride (5.5 g, 56 mmol) and acetic acid (50 mL) that had been degassed by bubbling SO₂ through it for 1 hour at 0° C. After 4 hours, the mixture was warmed to room temperature, and then saturated aqueous sodium bicarbonate solution was added. After 20 minutes, the aqueous portion was extracted with ethyl acetate and these extractions resulted in several organic fractions which were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound as a yellow oil (3 g, 38%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.27-8.19 (m, 1H), 2.46 (s, 3H).

Step B: 3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. The title compound (1.6 g) was prepared using analogous conditions as described the preparation of in Intermediate 76 using 2-chloro-5-methylpyridine-3-sulfonyl chloride instead of 2-fluorobenzene-1-sulfonyl chloride in Step A and TFA in dichloromethane instead of 4 M HCl in methanol in Step B. MS (ESI): mass calcd. for C₁₂H₁₇N₃O₂S, 267.1; m/z found, 267.9 [M+H]⁺.

Step C: (*S)-3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. The mixture of 3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide isomers from Step B were separated by chiral SFC (stationary phase: Chiralpak AD 10 μm 5×25 cm; mobile phase: 40% ethanol, 60% CO₂ with 0.1% NH₃) to afford two enantiomers. The first eluting isomer (370 mg) was designated (*S): MS (ESI): mass calcd. for C₁₂H₁₇N₃O₂S, 267.1; m/z found, 268.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11-8.07 (m, 1H), 8.05-7.99 (m, 1H), 7.72-7.66 (m, 1H), 4.19-4.06 (m, 2H), 3.47-3.38 (m, 1H), 3.32-3.24 (m, 1H), 3.19-3.10 (m, 1H), 2.18 (s, 3H), 1.72-1.49 (m, 6H).

Intermediate 78: (*S)-3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: 2-Chloro-5-fluoropyridin-3-amine. Iron (15 g, 270 mmol) was added in portions to a solution of 2-chloro-5-fluoro-3-nitropyridine (12 g, 68 mmol) and acetic acid (200 mL). The mixture was warmed to 80° C. After 30 minutes, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was suspended in ethyl acetate and the suspension filtered through a pad of diatomaceous earth. The filtrate was brought to neutral pH by the addition of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and these extractions resulted in several organic fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound as a white solid which was used in the next step without further purification (11 g). MS (ESI): mass calcd. for C₅H₄ClFN₂, 146.0; m/z found, 146.8 [M+H]⁺.

Step B: 3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. The title compound (11 g) was prepared using analogous conditions as described in Intermediate 77 using 2-chloro-5-fluoropyridin-3-amine instead of 2-chloro-5-methylpyridin-3-amine in Step A. MS (ESI): mass calcd. for C₁₁H₁₄FN₃O₂S, 271.1; m/z found, 271.9 [M+H]⁺.

Step C: (*S)-3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. The mixture of 3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide isomers prepared in Step B were separated by chiral SFC (stationary phase: Chiralpak AS 10 μm 5×25 cm; mobile phase: 30% ethanol, 70% CO₂ with 0.1% NH₃) to afford two enantiomers. The first eluting isomer (5.22 g) was designated (*S): MS (ESI): mass calcd. for C₁₁H₁₄FN₃O₂S, 271.1; m/z found, 272.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=3.2 Hz, 1H), 8.22 (br s, 1H), 7.86-7.74 (m, 1H), 4.20-4.08 (m, 2H), 3.47 (t, J=12.8 Hz, 1H), 3.30-3.22 (m, 1H), 3.21-3.11 (m, 1H), 1.71-1.48 (m, 6H).

Intermediate 79: (*R)-3-Fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (4.95 g) from the separation of isomers by chiral SFC described in Intermediate 78 was designated (*R): MS (ESI): mass calcd. for C₁₁H₁₄FN₃O₂S, 271.1; m/z found, 272.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=2.8 Hz, 1H), 8.26-8.19 (m, 1H), 7.85-7.78 (m, 1H), 4.22-4.07 (m, 2H), 3.53-3.42 (m, 1H), 3.31-3.23 (m, 1H), 3.22-3.12 (m, 1H), 1.72-1.49 (m, 6H).

Intermediate 80: 8′-Fluoro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (2.2 g) was prepared using analogous conditions as described in Intermediate 78 using 1-(aminomethyl)cyclopropan-1-ol instead of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate in Step B. MS (ESI): mass calcd. for C₉H₉FN₂O₃S, 244.0; m/z found, 245.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=3.0 Hz, 1H), 7.99-7.95 (m, 1H), 5.02-4.87 (m, 1H), 3.70 (d, J=7.0 Hz, 2H), 1.29-1.17 (m, 2H), 0.82-0.67 (m, 2H).

Intermediate 81: 4,4-Dimethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

The title compound (238 mg) was prepared using analogous conditions as described in Intermediate 7 using 1-amino-2-methylpropan-2-ol instead of 3-(aminomethyl)oxetan-3-ol in Step A. MS (ESI): mass calcd. for C₁₀H₁₃NO₃S, 227.1; m/z found, 228.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J=7.8, 1.7 Hz, 1H), 7.45 (td, J=7.8, 1.7 Hz, 1H), 7.20 (td, J=7.7, 1.2 Hz, 1H), 7.09 (dd, J=8.0, 1.2 Hz, 1H), 4.85-4.74 (m, 1H), 3.61-3.40 (m, 2H), 1.29 (s, 6H).

Intermediate 82: 4,4-Dimethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

The title compound (139 mg) was prepared using analogous conditions as described in Intermediate 5 using 1-amino-2-methylpropan-2-ol instead of 1-(aminomethyl)cyclopropanol in Step A. MS (ESI): mass calcd. for C₉H₁₂N₂O₃S, 228.1; m/z found, 229.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (dd, J=4.9, 2.0 Hz, 1H), 8.30 (s, 1H), 8.11 (dd, J=7.6, 2.0 Hz, 1H), 7.36 (dd, J=7.6, 4.8 Hz, 1H), 3.43 (s, 2H), 1.21 (s, 6H).

Intermediate 83: (R)-6,7,7a,8,9,10-Hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

Step A: (R)-2-Fluoro-N-(pyrrolidin-2-ylmethyl)benzenesulfonamide. A mixture of 2-fluorobenzenesulfonamide (11.2 g, 64.2 mmol), (R)-pyrrolidin-2-ylmethanol (19 g, 188 mmol) in DMSO (33 mL) was warmed to 150° C. After 2.5 hours, the mixture was cooled to room temperature and then ethyl acetate was added. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated sodium chloride solution. The organic layers were dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane-ethyl acetate) to provide the title compound (5.5 g, 33%). Impure product fractions were concentrated, triturated with dichloromethane, filtered, and the solids collected to obtain an additional portion of the title compound (5.4 g, 33%). MS (ESI): mass calcd. for C₁₁H₁₆N₂O₃S, 256.1; m/z found, 257.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.08-7.99 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.37-7.27 (m, 1H), 5.96 (s, 2H), 3.78-3.51 (m, 4H), 2.88 (s, 1H), 2.66 (s, 1H), 2.19-1.91 (m, 4H).

Step B: (R)-6,7,7a,8,9,10-Hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. Di-tert-butyl azodicarboxylate (5.6 g, 24 mmol) was added to a stirring slurry of (R)-2-fluoro-N-(pyrrolidin-2-ylmethyl)benzenesulfonamide (5.2 g, 20 mmol) and triphenylphosphine (8 g, 30 mmol) in dichloromethane (104 mL). After 30 minutes, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (dichloromethane-ethyl acetate) to provide the title compound (1.5 g, 31%). MS (ESI): mass calcd. for C₁₁H₁₄N₂O₂S, 238.1; m/z found, 238.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (dd, J=8.0, 1.7 Hz, 1H), 7.40 (ddd, J=8.6, 7.1, 1.6 Hz, 1H), 7.00-6.90 (m, 2H), 4.84 (s, 1H), 4.16 (s, 1H), 3.55-3.35 (m, 3H), 3.18-3.02 (m, 1H), 2.21-1.99 (m, 3H), 1.83-1.73 (m, 1H).

Intermediate 84: (S)-6,7,7a,8,9,10-Hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

The title compound (1.7 g) was prepared using analogous conditions as described in Intermediate 83 using (S)-pyrrolidin-2-ylmethanol instead of (R)-pyrrolidin-2-ylmethanol in Step A. MS (ESI): mass calcd. for C₁₁H₁₄N₂O₂S, 238.1; m/z found, 239.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.79-7.71 (m, 1H), 7.67 (dd, J=7.9, 1.6 Hz, 1H), 7.38 (ddd, J=8.6, 7.1, 1.7 Hz, 1H), 7.00-6.94 (m, 1H), 6.90 (ddd, J=8.0, 7.1, 1.1 Hz, 1H), 3.86-3.74 (m, 1H), 3.37-3.24 (m, 2H), 3.17 (ddd, J=13.4, 4.7, 3.3 Hz, 1H), 2.95 (ddd, J=13.3, 11.6, 7.8 Hz, 1H), 2.12-1.82 (m, 3H), 1.67 (ddt, J=12.2, 6.0, 1.8 Hz, 1H).

Intermediate 85: (*S)-9-Methyl-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: 4-Benzyl 1-(tert-butyl) 2-carbamoylpiperazine-1,4-dicarboxylate. NH₄HCO₃ (9 g, 114 mmol) was added to a solution of 4-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (33 g, 91 mmol), Boc₂O (25.7 g, 118 mmol), pyridine (4.3 g, 54 mmol), and 1,4-dioxane (462 mL). After 14 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and the solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title compound (36 g). This material was used in the next step without further purification. MS (ESI): mass calcd. for C₁₈H₂₅N₃O₅, 363.2; m/z found, 386.0 [M+Na]⁺.

Step B: 4-Benzyl 1-(tert-butyl) 2-cyanopiperazine-1,4-dicarboxylate. The below reaction was run twice on 2 different scales: once using 10 g of 4-benzyl 1-tert-butyl 2-carbamoylpiperazine-1,4-dicarboxylate and once using 26 g. The 26 g scale reaction details are provided. TFAA (19.5 g, 93.0 mmol) was added to an icewater cooled solution of 4-benzyl 1-tert-butyl 2-carbamoylpiperazine-1,4-dicarboxylate (26 g, 72 mmol), Et₃N (23 g, 230 mmol), and THF (260 mL). The resulting mixture was stirred for 2 hours with gradual warming to room-temperature and then combined with a similar reaction mixture as described above starting with 10 g of 4-benzyl 1-tert-butyl 2-carbamoylpiperazine-1,4-dicarboxylate. The combined mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum etherethyl acetate, 10:1 to 2:1, gradient elution) to afford the title compound (26 g) as a light yellow oil. MS (ESI): mass calcd. for C₁₈H₂₃N₃O₄, 345.2; m/z found, 345.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.29 (m, 5H), 5.24-4.98 (m, 3H), 4.54-4.16 (m, 2H), 3.95 (br s, 1H), 3.24-3.01 (m, 2H), 2.88 (br s, 1H), 1.49 (s, 9H).

Step C: 4-Benzyl 1-(tert-butyl) 2-(aminomethyl)piperazine-1,4-dicarboxylate. The below reaction was run twice on 2 different scales: 4-benzyl 1-tert-butyl 2-cyanopiperazine-1,4-dicarboxylate and a second using 16 g of 4-benzyl 1-tert-butyl 2-cyanopiperazine-1,4-dicarboxylate. The details for the 16 g reaction are shown below. NaBH₄ (17.5 g, 463 mmol) was added in portions to an icewater cooled solution of 4-benzyl 1-tert-butyl 2-cyanopiperazine-1,4-dicarboxylate (16 g, 46 mmol) and CoCl₂ (22 g, 93 mmol), and MeOH (347 mL). The mixture was allowed to warm to room temperature. After 2 hours, the mixture was combined with the reaction mixture as described above starting with 10 g of 4-benzyl 1-tert-butyl 2-cyanopiperazine-1,4-dicarboxylate. The mixture was diluted with ethyl acetate (300 mL) and the suspension filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane which resulted in several organic fractions. These fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title compound (21 g) as a dark yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₈H₂₇N₃O₄, 349.2; m/z found, 350.0 [M+H]⁺.

Step D: 4-Benzyl 1-(tert-butyl) 2-(((2-chloropyridine)-3-sulfonamido)methyl)piperazine-1,4-dicarboxylate. K₂CO₃ (5.44 g, 39.4 mmol) was added to a mixture of 4-benzyl 1-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylate (11.5 g), THF (124 mL), and H₂O (31 mL). After 5 minutes, 2-chloropyridine-3-sulfonyl chloride (6.96 g, 32.8 mmol) was added in portions. After 2 hours, the mixture was extracted with ethyl acetate which resulted in numerous organic fractions. These fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title compound (18 g) which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₃H₂₉ClN₄O₆S, 524.2; m/z found, 547.0 [M+Na]⁺.

Step E: Benzyl 3-(((2-chloropyridine)-3-sulfonamido)methyl)piperazine-1-carboxylate 2,2,2-trifluoroacetate. TFA (20.0 mL, 269 mmol) was added to a solution of 4-benzyl 1-tert-butyl 2-((2-chloropyridine-3-sulfonamido)methyl)piperazine-1,4-dicarboxylate (13.0 g, 24.8 mmol) and methylene chloride (100 mL). After 2 hours, the mixture was concentrated under reduced pressure to afford the title compound (14.5 g) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₈H₂₁ClN₄O₄S, 424.1; m/z found, 425.0 [M+H]⁺.

Step F: Benzyl 6,7,7a,8,10,11-hexahydro-9H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine-9-carboxylate 5,5-dioxide. Cs₂CO₃ (43.8 g, 134 mmol) was added to a solution of benzyl 3-((2-chloropyridine-3-sulfonamido)methyl)piperazine-1-carboxylate 2,2,2-trifluoroacetate (14.5 g) and DMSO (250 mL). The mixture was warmed to 160° C. After 6 hours, the mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (350 mL) and washed with water. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1 to 2:1, gradient elution) to afford the title compound (4.5 g, 43%) as a yellow oil. MS (ESI): mass calcd. for C₁₈H₂₀N₄O₄S, 388.1; m/z found, 389.0 [M+H]⁺.

Step G: 7,7a,8,9,10,11-Hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. Benzyl 6,7,7a,8,10,11-hexahydro-9H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine −9-carboxylate 5,5-dioxide (4.0 g, 10 mmol), MeOH (200 mL), and Pd(OH)₂ on carbon (2.0 g, 10 wt. %, 1.4 mmol) were added to a 500-mL round-bottomed flask. The mixture was stirred under a H₂ atmosphere (15 psi) at room temperature. After 1 hour, the suspension was filtered through a pad of diatomaceous earth and the pad washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (2.5 g) as a white solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₀H₁₄N₄O₂S, 254.1; m/z found, 255.1 [M+H]⁺.

Step H: (*S)-9-Methyl-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. NaBH₃CN (3.7 g, 59 mmol) was added in portions to an icewater cooled solution of 7,7a,8,9,10,11-Hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (2.5 g), 37% aqueous formaldehyde (16 g, 197 mmol), MeOH (100 mL), and dichloromethane (50 mL). The mixture was allowed to warm to room temperature. After 1 hour, the mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous layer was extracted with ethyl acetate. This resulted in several organic fractions which were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 250×50 mm×10 μm column, eluent: 5% to 25% (v/v) CH₃CN in H₂O with 0.05% NH₃) to afford the title compound as a racemic mixture as a pink solid (900 mg, 33%). This was combined with an additional 750 mg of the racemic mixture (1.6 g total). A second purification was performed by preparative liquid chromatography (irregular bare silica, 5% methanol in dichloromethane with 0.5% NH₄OH) to provide the title compound (1.4 g) as the racemic mixture. The isomers were separated by chiral SFC (stationary phase: Chiralcel OD-H 5 μm 250×30 mm, mobile phase: 80% CO₂ and 20% ethanol) to afford two enantiomers. The first eluting enantiomer (625 mg) was designated (*S). MS (ESI): mass calcd. for C₁₁H₁₆N₄O₂S, 268.1; m/z found, 268.9 [M+H]⁺.

Intermediate 86: (*R)-9-Methyl-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (650 mg) from the separation of isomers by chiral SFC described in Intermediate 85 was designated (*R). MS (ESI): mass calcd. for C₁₁H₁₆N₄O₂S, 268.1; m/z found, 268.9 [M+H]⁺.

Intermediate 87: (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide

Step A: tert-Butyl (R)-2-(((2,5-dichloropyridine)-3-sulfonamido)methyl)pyrrolidine-1-carboxylate. tert-Butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate (2.44 g, 12.2 mmol) was added to a suspension consisting of K₂CO₃ (1.18 g, 8.52 mmol), THF (27 mL), and H₂O (5.5 mL) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C. and then treated with 2,5-dichloropyridine-3-sulfonyl chloride (2.0 g, 8.1 mmol). The resulting mixture was stirred at room temperature for 6.5 hours and concentrated to dryness under reduced pressure. The residue was dissolved in water (20 mL) and the aqueous layer was extracted with ethyl acetate (20 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (3.0 g, 90%) as a yellow solid. MS (ESI): mass calcd. for C₁₅H₂₁Cl₂N₃O₄S, 409.1; m/z found, 310.1 [M-100]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47 (d, J=2.5 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H), 7.51 (s, 1H), 4.09 (q, J=7.1 Hz, 1H), 4.01-3.95 (m, 1H), 3.42-3.33 (m, 1H), 3.25 (dt, J=11.5, 6.3 Hz, 1H), 3.20-3.12 (m, 1H), 2.94-2.85 (m, 1H), 2.08-1.96 (m, 2H), 1.85-1.72 (m, 1H), 1.43 (s, 9H).

Step B: (R)-3-Chloro-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. TFA (5 mL) was added dropwise to a solution of tert-butyl (R)-2-(((2,5-dichloropyridine)-3-sulfonamido)methyl)pyrrolidine-1-carboxylate (3.0 g, 7.3 mmol) and dichloromethane (20 mL) at 0° C. The resulting mixture was stirred for 16 hours with gradual warming to room temperature. It was then concentrated to dryness under reduced pressure. TEA (6.2 mL, 44 mol) was added to the residue in toluene (33 mL). The resulting solution was stirred at refluxing temperature for 16 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (2.0 g, 99%) as a yellow solid. MS (ESI): mass calcd. for C₁₀H₁₂ClN₃O₂S, 273.0; m/z found, 274.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.16-8.09 (m, 1H), 7.83 (dd, J=5.3, 2.5 Hz, 1H), 5.84 (d, J=11.6 Hz, 1H), 4.46-4.35 (m, 1H), 4.15-4.00 (m, 2H), 3.61 (p, J=4.8 Hz, 2H), 3.49-3.39 (m, 1H), 3.17-3.03 (m, 1H), 2.15-2.05 (m, 1H), 1.76-1.68 (m, 1H).

Step C: (R)-6,7,7a,8,9,10-Hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide. Zn(CN)₂ (1.47 g, 12.5 mmol) was added to a mixture of (R)-3-chloro-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (2.0 g, 7.3 mmol), Zn (185 mg, 2.83 mmol), and DMA (42 mL). The mixture was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl₂ (631 mg, 0.69 mmol) and X-Phos (526 mg, 1.10 mmol). The resultant mixture was sparged with Ar for another 5 minutes and then stirred at 110° C. for 18 hours before cooling to room temperature. The reaction mixture was filtered and the solid was rinsed with ethyl acetate (10 mL×2). The filtrate was concentrated to dryness under reduced pressure and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (1.7 g, 88%) as a brown solid. MS (ESI): mass calcd. for C₁₁H₁₂N₄O₂S, 264.1; m/z found, 264.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.39 (d, J=2.2 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 5.65 (dd, J=6.6, 3.8 Hz, 1H), 4.85-4.75 m, 1H), 3.86-3.65 (m, 2H), 3.56 (dt, J=12.9, 3.7 Hz, 1H), 3.20 (td, J=12.6, 6.5 Hz, 1H), 2.11-1.94 (m, 3H), 1.84-1.74 (m, 1H).

Intermediate 88: (S)-6,7,7a,8,9,10-Hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide

Step A: tert-Butyl (S)-2-(((2,5-dichloropyridine)-3-sulfonamido)methyl)pyrrolidine-1-carboxylate. tert-Butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate (2.44 g, 12.2 mmol) was added to a suspension consisting of K₂CO₃ (1.18 g, 8.52 mmol), THF (27 mL), and H₂O (5.5 mL) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C. and then treated with 2,5-dichloropyridine-3-sulfonyl chloride (2.0 g, 8.1 mmol). The resulting mixture was stirred at room temperature for 6.5 hours and concentrated to dryness under reduced pressure. The residue was dissolved in water (20 mL) and the aqueous layer was extracted with ethyl acetate (20 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (3.0 g, 90%) as a yellow solid. MS (ESI): mass calcd. for C₁₅H₂₁Cl₂N₃O₄S, 409.1; m/z found, 310.1 [M-100]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.44 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.49 (dd, J=6.4, 3.1 Hz, 1H), 3.93 (tt, J=8.4, 4.1 Hz, 1H), 3.33 (dt, J=10.9, 7.5 Hz, 1H), 3.22 (dt, J=11.6, 6.3 Hz, 1H), 3.15-3.07 (m, 1H), 2.92-2.83 (m, 1H), 2.04-1.91 (m, 2H), 1.83-1.69 (m, 2H), 1.39 (s, 9H).

Step B: (S)-3-Chloro-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. TFA (5 mL) was added dropwise to a solution of tert-butyl (S)-24(2,5-dichloropyridine)-3-sulfonamido)methyl)pyrrolidine-1-carboxylate (3.0 g, 7.3 mmol) and dichloromethane (20 mL) at 0° C. The resulting mixture was stirred for 16 hours with gradual warming to room temperature. It was then concentrated to dryness under reduced pressure. TEA (6.2 mL, 44 mol) was added to the residue in toluene (33 mL). The resulting solution was stirred at 130° C. for 16 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (2.0 g, 99%) as a yellow solid. MS (ESI): mass calcd. for C₁₀H₁₂ClN₃O₂S, 273.0; m/z found, 273.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J=2.5 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 6.00 (s, 1H), 4.44-4.35 (m, 1H), 3.68-3.53 (m, 2H), 3.43 (dd, J=13.1, 3.6 Hz, 1H), 3.10 (dd, J=13.1, 12.1 Hz, 1H), 2.03-1.88 (m, 3H), 1.76-1.67 (m, 1H).

Step C: (S)-6,7,7a,8,9,10-Hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide. Zn(CN)₂ (1.47 g, 12.5 mmol) was added to a mixture of (R)-3-chloro-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (2.0 g, 7.3 mmol), Zn (185 mg, 2.83 mmol), and DMA (42 mL). The mixture was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl₂ (631 mg, 0.69 mmol) and X-Phos (526 mg, 1.10 mmol). The resultant mixture was sparged with Ar for another 5 minutes and then stirred at 110° C. for 18 hours before cooling to room temperature. The reaction mixture was filtered and the solid was rinsed with ethyl acetate (10 mL×2). The filtrate was concentrated to dryness under reduced pressure and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (1.7 g, 87%) as a brown solid. MS (ESI): mass calcd. for C₁₁H₁₂N₄O₂S, 264.1; m/z found, 264.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.42 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 5.50 (s, 1H), 4.87-4.75 (m, 1H), 3.86-3.64 (m, 2H), 3.58 (dt, J=12.9, 3.5 Hz, 1H), 3.20 (td, J=12.5, 6.2 Hz, 1H), 2.25-2.15 (m, J=12.7, 11.4, 8.6, 6.7 Hz, 1H), 2.12-1.93 (m, 2H), 1.84-1.75 (m, 1H).

Intermediate 89: (*S)-3-Chloro-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

(*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 13, 300 mg, 1.18 mmol) was dissolved in DCM (24 mL). At room temperature, N-chlorosuccinimide (314 mg, 2.35 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was dissolved in water (10 mL) and the aqueous layer was extracted with ethyl acetate (10 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (200 mg, 59%) as a yellow solid. MS (ESI): mass calcd. for C₁₀H₁₂ClN₃O₃S, 289.0; m/z found, 290.0 [M+1]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.14 (d, J=2.5 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H), 5.88-5.83 (m, 1H), 4.37-4.28 (m, 2H), 4.10-4.00 (m, 1H), 3.84 (td, J=13.0, 6.4 Hz, 1H), 3.79-3.71 (m, 2H), 3.70 (dd, J=12.2, 2.0 Hz, 1H), 3.55-3.47 (m, 1H), 3.42 (dt, J=13.4, 4.5 Hz, 1H).

Intermediate 90: Ethyl 3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Step A: 1-Cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole. A mixture of 5-bromo-1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 29, 135 mg, 0.54 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (166 mg, 0.64 mmol), KOAc (158 mg, 1.61 mmol), and dioxane (15 mL) was sparged with N₂ for 5 minutes and then treated with Pd(dppf)Cl₂ (12 mg, 0.02 mmol). The mixture was sparged with N₂ for another 5 minutes and then stirred at 90° C. for 4 hours. After cooling to room temperature, the suspension was filtered through diatamaceous earth and washed with ethyl acetate (10 mL). The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (150 mg, 94%) as a white solid. MS (ESI): mass calcd. for C₁₆H₂₂BN₃O₂, 299.2; m/z found, 299.0 [M]⁺.

Step B: Ethyl 3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. 1-Cyclopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (258 mg, 0.86 mmol), triethylamine (0.12 mL, 0.86 mmol), and [Rh(COD)Cl]₂ (14 mg, 0.03 mmol) were added to a solution of ethyl (E)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)acrylate (Intermediate 15, 150 mg, 0.57 mmol) in 1,4-dioxane (4 mL) and water (2 mL). The reaction mixture was stirred at 95° C. for 2 hours. After this time, the reaction was cooled to room temperature, then diluted with water and ethyl acetate. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-20% ethyl acetate/hexanes) to afford the title compound (50 mg, 20% yield). MS (ESI): mass calcd. for C₂₄H₂₈N₄O₄, 436.2; m/z found, 437.0 [M+H]⁺.

Intermediate 91: (R)-4-Ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

Step A: (R)-1-Aminobutan-2-ol. (R)-2-Ethyloxirane (6.0 g, 83 mmol) and 28% aqueous NH₃ (100 mL, 727 mmol) were added to a 250 mL three-necked round-bottomed flask.

The mixture was stirred at room temperature for 18 hours before concentrating to dryness under reduced pressure to afford the title compound (8 g) as a yellow oil, which was used in the next step without purification. ¹H NMR (400 MHz, CDCl₃) δ 3.47-3.38 (m, 1H), 2.85-2.74 (m, 1H), 2.57-2.48 (m, 4H), 1.50-1.35 (m, 2H), 0.93 (t, J=7.6 Hz, 3H).

Step B: (R)-2-Chloro-N-(2-hydroxybutyl) pyridine-3-sulfonamide. A solution of 2-chloropyridine-3-sulfonyl (20 g, 94 mmol) and THF (80 mL) was added dropwise to a 0° C. mixture of (R)-1-aminobutan-2-ol (8.0 g), K₂CO₃ (24.0 g, 173 mmol), THF (80 mL), and H₂O (40 mL). The mixture was stirred at room temperature for 12 hours, then concentrated to dryness under reduced pressure. The residue was diluted with water (150 mL) and the resultant mixture extracted with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (20 g) as a yellow oil, which was used in the next step without further purification. MS (ESI): mass calcd. C₉H₁₃ClN₂O₃S 264.03 m/z, found 264.8 [M+H]⁺.

Step C: (R)-4-Ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide. t-BuOK (25.0 g, 223 mmol) was added in portions to a 0° C. solution of (R)-2-chloro-N-(2-hydroxybutyl)pyridine-3-sulfonamide (20 g) and DMSO (100 ml). The mixture was heated at 80° C. for 12 hours before cooling to room temperature and concentrating to dryness under reduced pressure. The residue was diluted with H₂O (200 mL), and the resultant mixture acidified to pH 6 with 1 N HCl, and extracted with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC using a Xtimate C18, 150×25 mm×5 μm column (eluent: 5% to 35% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to afford the title compound (6 g). The product contained impurities and was triturated with petroleum ether: ethyl acetate (30:1, 100 mL) and the suspension isolated via filtration. The filter cake was washed with petroleum ether (50 mL) before drying under reduced pressure to afford the title compound (5.67 g) as a white solid. MS (ESI): mass calcd. for C₉H₁₂N₂O₃S 228.06 m/z, found 229.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.85 (d, J=5.2 Hz, 1H), 7.72-7.67 (m, 2H), 6.76-6.70 (m, 1H), 6.68-6.65 (m, 1H), 5.40 (s, 2H), 4.49 (t, J=6.4 Hz, 2H), 2.69 (t, J=6.4 Hz, 2H).

Intermediate 92: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)propanoate

Step A: 1-Chloro-3-(difluoromethyl)-2-nitrobenzene. Diethylamino sulfurtrifluoride (32.6 g, 202 mmol) was added to a 0° C. solution of 3-chloro-2-nitrobenzaldehyde (15 g, 81 mmol) and dichloromethane (200 mL). The mixture was stirred for 3 hours with gradual warming to room temperature before quenching with H₂O (200 mL) and extracting with dichloromethane (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate=1:0 to 20:1, gradient elution) to provide the title compound (12 g, 64%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.06-7.95 (m, 1H), 7.86-7.77 (m, 2H), 7.42-7.11 (m, 1H).

Step B: N-(Cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline. 1-Chloro-3-(difluoromethyl)-2-nitrobenzene (2.0 g, 9.6 mmol) and cyclopropylmethanamine (10 mL) were added to a 20 mL sealed tube. The mixture was stirred at 80° C. for 16 hours before cooling to room temperature. At that time the reaction mixture was quenched with water (60 mL), and extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 5:1, gradient elution) to give the title compound (2.1 g, 90%) as a red solid.

Step C: 4-Bromo-N-(cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline. N-(Cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline (2.1 g, 8.7 mmol), NBS (1.54 g, 8.65 mmol), and DMF (10 mL) were added to a 50 mL round-bottomed flask. The mixture was stirred at room temperature for 4 hours before quenching with water (50 mL) and extracting with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 5:1, gradient elution) to give the title compound (2.1 g, 68%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, J=9.0 Hz, 1H), 7.09-6.79 (m, 2H), 6.22 (t, J=5.6 Hz, 1H), 2.86 (t, J=6.2 Hz, 2H), 0.91-0.79 (m, 1H), 0.28-0.18 (m, 2H), 0.05-0.04 (m, 2H).

Step D: 4-Bromo-N¹-(cyclopropylmethyl)-3-(difluoromethyl)benzene-1,2-diamine. Zn (3.4 g, 52 mmol) was added to a solution of 4-bromo-N-(cyclopropylmethyl)-3-(difluoromethyl)-2-nitroaniline (2.1 g, 6.5 mmol), NH₄Cl (5.60 g, 105 mmol), and THF (20 mL). The resultant mixture was stirred at room temperature for 16 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (60 mL). The filtrate was concentrated to dryness under reduced pressure to afford the title product (1.8 g, 95%) as a yellow solid. MS (ESI): mass calcd. for C₁₁H₁₃BrF₂N₂ 290.02, m/z found 292.8 [M+H]⁺.

Step E: 5-Bromo-1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazole. A solution of NaNO₂ (5.7 g, 83 mmol) and H₂O (10 mL) were added to a 0° C. mixture of 4-bromo-M-(cyclopropylmethyl)-3-(difluoromethyl)benzene-1,2-diamine (8.0 g, 27 mmol), 4-methylbenzenesulfonic acid hydrate (18.3 g, 96.2 mmol), and CH₃CN (100 mL). The resultant mixture was stirred at 0° C. for 3 hours before quenching with aq. NaHCO₃(300 mL) and extracting with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 5:1, gradient elution) to give the title compound (6.2 g, 75%) as a brown solid.

Step F: (E)-Ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. 5-Bromo-1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazole (2.0 g, 6.6 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (3.0 g, 13 mmol), and Na₂CO₃ (1.4 g, 13 mmol) were added to a 100 mL three-necked round-bottomed flask and the mixture dissolved in 1,4-dioxane (30 mL) and H₂O (6 mL). The mixture was sparged with Na for 5 minutes and then treated with Pd(dppf)Cl₂ (484 mg, 0.661 mmol). The mixture was sparged with Na for another 5 minutes and then stirred and heated at 100° C. for 16 hours before cooling to room temperature, quenching with water (60 mL) and extracting with ethyl acetate (40 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate, 20:1 to 5:1, gradient elution) to give the title compound (2.0 g, 80%) as a black solid. MS (ESI): mass calcd. for C₁₆H₁₇F₂N₃O₂ 321.13, m/z found 321.9 [M+H]⁺.

Step G: Ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. (E)-Ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (1.5 g, 4.7 mmol), (3-(hydroxymethyl)-4-methylphenyl)boronic acid (2.3 g, 14 mmol), aq. KOH (5.6 mL, 1.0 M, 5.6 mmol), and 1,4-dioxane (20 mL) were added to a 100 mL round-bottomed flask. The mixture was sparged with Na for 5 minutes and then treated with chloro(1,5-cyclooctadiene)rhodium(I) dimer (230 mg, 0.466 mmol). The reaction mixture was stirred at room temperature for 16 hours before quenching with H₂O (60 mL) and extracting with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by preparative basic HPLC using a Phenomenex Gemini C18 250 mm×50 mm, 10 μm column (eluent: 30% to 70% (v/v) CH₃CN and H₂O with 0.05% NH₃) to afford the title compound. MS (ESI): mass calcd. for C₂₄H₂₇F₂N₃O₃ 443.20, m/z found 444.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.75 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.18-7.12 (m, 1H), 7.07-7.01 (m, 1H), 5.17-5.07 (m, 1H), 5.01 (t, J=5.3 Hz, 1H), 4.58 (d, J=7.3 Hz, 2H), 4.43-4.35 (m, 2H), 3.97-3.88 (m, 2H), 3.28-3.19 (m, 1H), 3.14-3.05 (m, 1H), 2.14 (s, 3H), 1.38-1.26 (m, 1H), 1.01 (t, J=7.2 Hz, 3H), 0.55-0.39 (m, 4H).

Step H: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. Thionyl chloride (0.16 mL, 2.2 mmol) was added to a solution of ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. (502 mg, 1.1 mmol) in DCM (5.5 mL) and 2 drops of DMF. The reaction was stirred at room temperature for 5 minutes. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure, to provide the title compound which was used without further purification. MS (ESI): mass calcd. for C₂₄H₂₆ClF₂N₃O₂, 461.9; m/z found, 462.3 [M+H]⁺.

Intermediate 93: 5′-Methyl-2′,3′-dihydro-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepine] 1′,1′-dioxide

Step A: tert-Butyl (1-carbamoylcyclopropyl)carbamate. Pyridine(11.8 g, 149 mmol) was added drop-wise to a mixture consisting of 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (50.0 g, 248 mmol), Boc₂O (70.5 g, 323 mmol), NH₄HCO₃ (24.6 g, 311 mmol), and MeCN (500 mL) over a period of 10 minutes. The resultant mixture was stirred at room temperature for 16 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (100 mL), adjusted to pH 7 with 1 N HCl, and then the resultant mixture was extracted with ethyl acetate (300 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure, to provide the title compound (40.1 g, 80%) as a white solid, which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 6.42 (br. s, 1H), 5.71 (br. s, 1H), 5.18 (br. s, 1H), 1.61-1.56 (m, 2H), 1.46-1.45 (m, 9H), 1.09-0.98 (m, 2H).

Step B: tert-Butyl (1-cyanocyclopropyl)carbamate. TFAA (47.3 g, 225 mmol) was added drop-wise to solution consisting of tert-butyl (1-carbamoylcyclopropyl)carbamate (30.0 g, 150 mmol), triethylamine (62.7 g, 450 mmol), and dichloromethane (180 mL) over a period of 1 hour. The resultant mixture was stirred at room temperature for 4 hours before concentrating to dryness under reduced pressure to give the title compound, which was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 5:1, gradient elution) to afford the title compound (22.5 g, 82.3%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 6.60 (br s, 1H), 2.63 (s, 9H), 1.28 (s, 2H), 1.24-1.20 (m, 1H), 1.07-1.01 (m, 1H).

Step C: tert-Butyl (1-cyanocyclopropyl)(methyl)carbamate. Sodium hydride in mineral oil (15.0 g, 60% purity, 375 mmol) was added in portions to a 0° C. solution of tert-butyl (1-cyanocyclopropyl)carbamate (22.5 g, 123 mmol) and THF (150 mL). The resultant mixture was treated with iodomethane (34.7 g, 244 mmol) by dropwise addition at 0° C. and then stirred for 12 hours with gradual warming to room temperature before quenching with saturated aqueous NH₄Cl (100 mL) and extracting with ethyl acetate (150 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (100 mL), dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure, to provide the title compound (23.0 g), which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 2.90 (s, 3H), 1.48 (s, 9H), 1.27-1.26 (m, 2H), 0.86-0.82 (m, 2H).

Step D: tert-Butyl (1-(aminomethyl)cyclopropyl)(methyl)carbamate. Raney Ni (2 g) was added to a 1 L round-bottomed flask containing a mixture of tert-butyl (1-cyanocyclopropyl)(methyl)carbamate (23 g), methanol (200 mL), and 25% aqueous NH₃ (5 mL) which had been degassed with argon. The mixture was stirred under an atmosphere of H₂ (15 psi) at room temperature for 15 hours. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (150 mL). The filtrate was concentrated to dryness under reduced pressure to afford the title product (25 g), which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 2.86 (br s, 3H), 1.84-1.80 (m, 2H), 1.44 (br. s, 9H), 1.23-1.22 (m, 2H), 0.85-0.81 (m, 2H).

Step E: tert-Butyl (1-((2-chloropyridine-3-sulfonamido)methyl)cyclopropyl)(methyl)carbamate. A solution consisting of 2-chloropyridine-3-sulfonyl chloride (20 g, 94 mmol) and THF (50 mL) was added dropwise to a mixture of tert-butyl (1-(aminomethyl)cyclopropyl)(methyl)carbamate (20 g), K₂CO₃ (20.0 g, 145 mmol), THF (150 mL), and H₂O (40 mL) which had been cooled to 0° C. The resultant mixture was stirred for 12 hours with gradual warming to room temperature before concentrating to dryness under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL×2). These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure, to provide the title compound (30 g) as a yellow solid, which was used in the next step without purification. MS (ESI): mass calcd. for C₁₅H₂₂ClN₃O₄S 375.10 m/z, found 398.0 [M+Na]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.58-8.54 (m, 1H), 8.40-8.35 (m, 1H), 7.45-7.36 (m, 1H), 6.83 (br. s, 1H), 3.07-2.98 (m, 2H), 2.82 (s, 3H), 1.47 (s, 9H), 0.97-0.93 (m, 2H), 0.85-0.78 (m, 2H).

Step F: 2-Chloro-N-((1-(methylamino)cyclopropyl)methyl)pyridine-3-sulfonamide. TFA (30.0 mL, 433 mmol) was added to a 0° C. solution consisting of tert-butyl (1-((2-chloropyridine-3-sulfonamido)methyl)cyclopropyl)(methyl)carbamate (35 g) and dichloromethane (100 mL). The mixture was stirred for 2 hours with gradual warming to room temperature before concentrating to dryness under reduced pressure to afford the title compound (30 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₀H₁₄ClN₃O₂S 275.05, m/z found 275.9 [M+H]⁺.

Step G: 5′-Methyl-3′,5′-dihydro-2′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepine] 1′,1′-dioxide. DIPEA (30.0 mL, 172 mmol) was added dropwise to a solution of 2-chloro-N-((1-(methylamino)cyclopropyl)methyl)pyridine-3-sulfonamide (10 g) and DMSO (60 mL). The mixture was heated at 160° C. for 2 hours before cooling to room temperature and concentrating to dryness under reduced pressure. The residue was diluted with H₂O (200 mL) and the resultant solution extracted with ethyl acetate (150 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to give the product, which was triturated with ethyl acetate:petroleum ether (1:10). The suspension was isolated via filtration and the filter cake washed with ethyl acetate:petroleum ether (1:30) before drying under reduced pressure to afford the title compound (3.58 g, 41%). MS (ESI): mass calcd. for C₁₀H₁₃N₃O₂S 239.07 m/z, found 240.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.19 (m, 1H), 8.15-7.79 (m, 2H), 6.98-6.89 (m, 1H), 3.32-3.06 (m, 2H), 3.02 (s, 3H), 0.99-0.57 (m, 4H).

Intermediate 94: 2,5-Dichloropyridine-3-sulfonyl chloride

To a solution of 2,5-dichloropyridin-3-amine (50 g, 307 mmol) in CH₃CN (300 mL), which had been cooled to 0° C., was added fluoroboric acid (71.6 mL, 460 mmol, 40% purity) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. Then tert-butyl nitrite (44.3 g, 429 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The resulting solution was a diazonium salts solution. In a separate flask, H₂O (500 mL) was added to SOCl₂ (100 mL, 1.38 mol), dropwise, while keeping the inner temperature below 7° C., then the solution was stirred at 15° C. for 16 hours. CuCl (734 uL, 30.7 mmol) was added, then the previously prepared diazonium salts solution was added (diazonium salt solution was maintained at −5° C. during addition) dropwise at 0° C. The reaction was stirred at 0° C. for 1 hour. A gray suspension was obtained. The mixture was extracted with EtOAc (500 ml×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (600 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=15:1) to afford the title compound (65.0 g, 81.7% yield) as a yellow oil.

Intermediate 95: 3-Chloro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl 2-(((2,5-dichloropyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate. To a solution of 2,5-dichloropyridine-3-sulfonyl chloride (Intermediate 94, 38.3 g, 179 mL) in THF (550 mL) and H₂O (200 mL) was added K₂CO₃ (35.9 g, 260 mmol). A solution of 2,5-dichloropyridine-3-sulfonyl chloride (40.0 g, 162 mmol) in THF (250 mL) was added to the reaction mixture which had been cooled to 0° C. After warming to 20° C., the reaction mixture was stirred at 20° C. for 2 hours. A yellow suspension was obtained. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed with brine (600 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate, 3:1 with 1% of Et₃N) to provide the title compound (55.0 g, 76% yield) as a yellow solid.

Step B: 2,5-Dichloro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide. To a solution of tert-butyl 2-(((2,5-dichloropyridine)-3-sulfonamido)methyl)piperidine-1-carboxylate (55.0 g, 130 mmol) in DCM (500 mL) was added TFA (28.8 mL, 389 mmol), and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCE (200 mL) and the solution was concentrated under reduced pressure again. The material was stirred in MTBE (100 mL) for 30 minutes and the solid was collected by filtration to provide the title compound as its TFA salt (40.0 g, 70% yield) as a white solid.

Step C: 3-Chloro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. To a solution of 2,5-dichloro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide as its TFA salt (40.0 g, 91.3 mmol) in DMF (600 mL) was added Cs₂CO₃ (89.2 g, 274 mmol) and the reaction mixture was stirred at 120° C. for 4 hours. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (500 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with water (500 mL) and brine (500 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=5:1). The product was stirred in MTBE (60 mL) for 30 minutes and the solid was collected by filtration to provide the title compound (30 g).

Intermediate 96: 8′-Chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2,5-Dichloro-N-((l-hydroxycyclopropyl)methyl)pyridine-3-sulfonamide. To a solution of 1-(aminomethyl)cyclopropan-1-ol (35.0 g, 283 mmol, as its HCl salt) in THF (1 L) and H₂O (200 mL) was added K₂CO₃ (126 g, 913 mmol). A solution of 2,5-dichloropyridine-3-sulfonyl chloride (Intermediate 94, 90.0 g, 365 mmol) in THF (500 mL) was added to the reaction mixture which had been cooled to 0° C. and then the reaction mixture was stirred at 20° C. for 16 hours. A yellow solution was obtained. The reaction mixture was extracted with EtOAc (1 L×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (1 L), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by FCC (petroleum ether/ethyl acetate, 5:1) to provide the title compound (66.0 g, 60% yield) as a white solid.

Step B: 8′-Chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. To a solution of 2,5-dichloro-N-((1-hydroxycyclopropyl)methyl)pyridine-3-sulfonamide (33.0 g, 111 mmol) in DMSO (500 mL) was added aqueous K₂CO₃ (3 M, 111 mL), the reaction mixture was stirred at 100° C. for 16 hours. A colorless solution was obtained. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (500 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with water (500 mL) and brine (500 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was stirred in MTBE (100 mL) for 30 minutes, and the solid was collected by filtration to provide the title compound (30.0 g, 51% yield, 98% purity) as a white solid.

Intermediate 97: 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide

Step A: 6-Bromo-2-chloropyridine-3-sulfonyl chloride. HBF₄ (22.2 mL, 40 wt. % in water, 145 mmol) was added dropwise to a solution of 6-bromo-2-chloropyridin-3-amine (20.0 g, 96.4 mmol) and acetonitrile (100 mL) which had been cooled to 0° C. This mixture was stirred at 0° C. for 10 minutes before treating it with tert-butyl nitrite (17.2 mL, 145 mmol) dropwise. The resultant mixture was stirred at room temperature for another 2 hours. Copper(I) chloride (14.3 g, 144 mmol) and acetic acid (100 mL) were mixed in a separate flask. This mixture was cooled to 0° C., bubbled with SO₂ gas (>1.3 M) at 0° C. for 1 hour. The copper(I) chloride in acetic acid mixture was cooled to 0° C. and was then treated with the above 6-bromo-2-chloropyridine-3-diazonium tetrafluoroborate solution dropwise. This mixture was stirred for 16 hours with gradual warming to room temperature. The suspension was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 10:1, gradient elution) to afford the title compound (11.4 g) as a brown liquid, which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (br s, 1H), 8.29-7.95 (m, 2H), 7.74-7.46 (m, 2H).

Step B: tert-Butyl 2-((6-bromo-2-chloropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate. 6-Bromo-2-chloropyridine-3-sulfonyl chloride (11.4 g, 39.2 mmol) was added to a 250 mL three-necked round-bottomed flask containing a mixture of K₂CO₃ (16.3 g, 118 mmol), THF (50 mL), and H₂O (10 mL) which had been cooled to 0° C. The resultant mixture was stirred for 10 minutes at 0° C. before treating with tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (8.4 g, 39 mmol). This mixture was stirred at room temperature for 8 hours and then concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 3:2, gradient elution) to afford the title compound (10.7 g) as a yellow solid. MS (ESI): mass calcd. for C₁₆H₂₃BrClN₃O₄S 467.03 m/z found 369.8 [M-100+H]⁺.

Step C: 6-Bromo-2-chloro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide. TFA (11.4 mL, 164 mmol) was added dropwise to a 100 mL round-bottomed flask containing a solution consisting of tert-butyl 2-((6-bromo-2-chloropyridine-3-sulfonamido)methyl)piperidine-1-carboxylate (7.70 g, 16.4 mmol) and dichloromethane (20 mL) which had been cooled to 0° C. The resultant mixture was stirred for 6 hours with gradual warming to room temperature before concentrating to dryness under reduced pressure to afford the title compound (8.3 g) as a brown liquid, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₁H₁₅BrClN₃O₂S 366.98 m/z found 369.8 [M+H]⁺.

Step D: 2-Bromo-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. DIPEA (42.2 mL, 310 mmol) was added to a mixture of 6-bromo-2-chloro-N-(piperidin-2-ylmethyl)pyridine-3-sulfonamide (8.3 g, 17 mmol) and toluene (20 mL). The reaction mixture was heated at 130° C. for 2 hours before cooling to room temperature. The mixture was concentrated to dryness under reduced pressure and then purified by FCC (petroleum ether:ethyl acetate, 1:0 to 1:1, gradient elution) to afford the title compound (7.6 g) as a yellow solid. MS (ESI): mass calcd. for C₁₁H₁₄BrN₃O₂S 331.00 m/z found 333.7 [M+H]⁺.

Step E: 7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide. Zn(CN)₂ (5.4 g, 46 mmol) was added to a 250 mL round-bottomed flask containing a mixture of 2-bromo-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (7.6 g, 23 mmol), Zn (310 mg, 4.74 mmol), and DMF (30 mL). The mixture was sparged with argon for 5 minutes and then treated with Pd(dppf)Cl₂ (1.8 g, 2.5 mmol). The mixture was then sparged with argon for another 5 minutes and heated at 140° C. for 3 hours before cooling to room temperature. The suspension was filtered through a pad of diatomaceous earth, the filtrate poured into water (50 mL), and the filtrate water mixture was extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure and purified by FCC (petroleum ether:ethyl acetate, 10:1 to 3:7, gradient elution) to afford the title compound (5.6 g, 86%) as a green solid. MS (ESI): mass calcd. for C₁₂H₁₄N₄O₂S 278.08 m/z found 278.9 [M+H]⁺.

Intermediate 98: (*S)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide

7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide (Intermediate 97) was purified by SFC over AD 250 mm×50 mm, 10 μm (eluent: 40% to 40% (v/v) supercritical CO₂ in EtOH and H₂O with 0.1% NH₃) to afford two diastereomers. The first eluting isomer (1.974 g) was designated (*S): MS (ESI): mass calcd. for C₁₂H₁₄N₄O₂S 278.08 m/z found 279.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.00 (d, J=8.0 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 5.25-5.14 (m, 1H), 4.49-4.37 (m, 1H), 4.37-4.26 (m, 1H), 3.57-3.42 (m, 2H), 3.40-3.27 (m, 1H), 1.87-1.73 (m, 3H), 1.69-1.58 (m, 3H).

Intermediate 99: (*R)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide

The second eluting isomer (1.9 g) from the separation of isomers by chiral SFC described in Intermediate 98 was designated (*R): MS (ESI): mass calcd. for C₁₂H₁₄N₄O₂S 278.08 m/z found 279.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.00 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 5.22-5.15 (m, 1H), 4.46-4.38 (m, 1H), 4.35-4.28 (m, 1H), 3.53-3.41 (m, 2H), 3.38-3.28 (m, 1H), 1.87-1.73 (m, 3H), 1.68-1.58 (m, 3H). Alternatively, the ¹H NMR was run in DMSO-d₆ and the data is as follows: ¹H NMR (400 MHz, DMSO-d₆) δ 8.39-8.32 (m, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 4.29-4.12 (m, 2H), 3.53-3.43 (m, 1H), 3.30-3.25 (m, 1H), 3.23-3.15 (m, 1H), 1.74-1.46 (m, 5H), 1.76-1.45 (m, 1H).

Intermediate 100: 3-(Trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,51 thiadiazepine 5,5-dioxide

Step A: 2-Chloro-5-(trifluoromethyl)pyridine-3-diazonium tetrafluoroborate. HBF₄ (11.7 mL, 40 wt. % in water, 76.2 mmol) was added dropwise to a mixture of 2-chloro-5-(trifluoromethyl)pyridin-3-amine (10 g, 51 mmol) and acetonitrile (80 mL) that had been cooled to 0° C. After 10 minutes, tert-butyl nitrite (9.1 mL, 77 mmol) was added drop-wise under N₂ atmosphere. The resultant mixture was stirred at room temperature for 2 hours. The mixture was used in the next step without further purification.

Step B: 2-Chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride. Copper(I) chloride (7.6 g, 77 mmol) and acetic acid (150 mL) was cooled to 0° C., bubbled with SO₂ gas (>1.3 M) at 0° C. for 1 hour, and then treated with the 2-chloro-5-(trifluoromethyl)pyridine-3-diazonium tetrafluoroborate solution dropwise at 0° C. under N₂ atmosphere. This reaction mixture was stirred for 16 hours with gradual warming to room temperature. The suspension was filtered through a pad of diatomaceous earth and the filtrate concentrated to dryness under reduced pressure to give the product, which was further purified by FCC (petroleum ether: ethyl acetate, 1:0) to afford the title compound (12.1 g) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80-8.76 (m, 1H), 8.38 (d, J=2.0 Hz, 1H).

Step C: tert-Butyl 2-((2-chloro-5-(trifluoromethyl)pyridine-3-sulfonamido)methyl)piperidine-1-carboxylate. tert-Butyl 2-(aminomethyl)piperidine-1-carboxylate (7.35 g, 34.3 mmol) was added to a suspension of K₂CO₃ (17.8 g, 129 mmol), THF (80 mL), and H₂O (16 mL) which had been cooled to 0° C. This reaction mixture was stirred for 10 minutes at 0° C. and then treated with 2-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (12 g, 43 mmol). The mixture was stirred at 0° C. for 2.5 hours before concentrating to dryness under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 3:2, gradient elution) to afford the title compound (12 g, 61%) as a brown liquid. MS (ESI): mass calcd. for C₁₇H₂₃ClF₃N₃O₄S 457.10 m/z found 357.9 [M-100+H]⁺.

Step D: 2-Chloro-N-(piperidin-2-ylmethyl)-5-(trifluoromethyl)pyridine-3-sulfonamide. TFA (18.2 mL, 263 mmol) was added dropwise to solution consisting of tert-butyl 2-((2-chloro-5-(trifluoromethyl)pyridine-3-sulfonamido)methyl)piperidine-1-carboxylate (12 g, 26 mmol) and dichloromethane (30 mL) that had been cooled to a 0° C. This mixture was stirred for 16 hours with gradual warming to room temperature before concentrating to dryness under reduced pressure to give the product (14 g) as a brown liquid, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₂H₁₅ClF₃N₃O₂S 357.05 m/z found 357.9 [M+H]⁺.

Step E: 3-(Trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. DIPEA (48.0 mL, 352 mmol) was added to a mixture of 2-chloro-N-(piperidin-2-ylmethyl)-5-(trifluoromethyl)pyridine-3-sulfonamide (14 g) and toluene (30 mL). The resultant mixture was stirred at 130° C. for 2 hours before cooling to room temperature and concentrating to dryness under reduced pressure. The material was purified by FCC (petroleum ether:ethyl acetate, 1:0 to 3:1, gradient elution) to provide the title compound (7.2 g, 94%) as a yellow solid. MS (ESI): mass calcd. for C₁₂H¹⁴F₃N₃O₂S 321.08 m/z found 321.9 [M+H]⁺.

Intermediate 101: (*S)-3-(Trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

3-(Trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 100, 7.2 g, 17 mmol) was purified by SFC over OD 250 mm×50 mm, 10 μm (eluent: 20% to 20% (v/v) supercritical CO₂ in EtOH and H₂O with 0.1% NH₃) to afford two diastereomers. The first eluting isomer (3.0 g) was designated (*S): MS (ESI): mass calcd. for C₁₂H₁₄F₃N₃O₂S 321.08 m/z found 322.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58-8.53 (m, 1H), 8.31 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 4.39-4.29 (m, 2H), 3.50 (t, J=13.2 Hz, 1H), 3.38-3.31 (m, 1H), 3.22 (dd, J=3.6, 3.6 Hz, 1H), 1.76-1.45 (m, 6H).

Intermediate 102: (*R)-3-(Trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (3.6 g) from the separation of isomers by chiral SFC described in Intermediate 101 was designated (*R): MS (ESI): mass calcd. for C₁₂H₁₄F₃N₃O₂S 321.08 m/z found 322.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56-8.54 (m, 1H), 8.30 (br s, 1H), 8.05 (d, J=2.4 Hz, 1H), 4.39-4.30 (m, 2H), 3.50 (t, J=13.2 Hz, 1H), 3.39-3.31 (m, 1H), 3.22 (dd, J=3.6, 3.6 Hz, 1H), 1.75-1.46 (m, 6H).

Intermediate 103: Ethyl (E)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate

Step A: 4-Bromo-2-hydrazinylpyridine. An emulsion of 4-bromo-2-fluoropyridine (33 g, 188 mmol) and hydrazine monohydrate (91 mL, 1876 mmol) was stirred at room temperature for 16 hours. 4M aqueous NaOH (81 mL) and water (165 mL) were added and the mixture was stirred at room temperature for 10 minutes. The precipitate was collected and washed with water (200 mL) to provide the title compound (34 g, 97%) as a white powder which was used in the next step without further purification.

Step B: N-(4-Bromopyridin-2-yl)acetohydrazide. Acetic anhydride (17 mL, 180 mmol) was added dropwise to a solution of 4-bromo-2-hydrazinylpyridine (33.9 g, 180 mmol) and triethyl amine (27.7 mL, 199 mmol) in DCM (340 mL) that had been cooled to 0° C. The reaction was stirred at 0° C. for 1 hour. After this period of time, the reaction mixture was diluted with saturated aqueous NaHCO₃(400 mL). The precipitate was collected and washed with saturated aqueous NaHCO₃(600 mL) to provide the title compound (37.6 g, 91%%) as a white powder which was used in the next step without further purification.

Step C: 7-Bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine. A solution of N-(4-bromopyridin-2-yl)acetohydrazide (37.5 g, 163 mmol) in acetic acid (380 mL) was stirred at 100° C. for 72 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was tritiated with saturated aqueous NaHCO₃(300 mL). The solid was washed with water (100 mL) and diethyl ether (50 mL) to provide the title compound (31 g, 90%) as a pale yellow solid which was used in the next step without further purification.

Step D: Ethyl (E)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. A mixture of 7-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (5 g, 24 mmol), ethyl acrylate (5.1 mL, 47 mmol), Pd(dppf)Cl₂ (1.73 g, 2.36 mmol), and triethyl amine (13.2 mL, 94.7 mmol) was stirred in DMF (50 mL) at 120° C. for 4 hours. The reaction mixture was cooled to room temperature and the precipitate was collected. The solid was washed with DMF (10 mL) to provide the title compound (5.12 g, 94%) as an off-white solid. MS (ESI): mass calcd. for C₁₂H₁₃N₃O₂, 231.1; m/z found, 232.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (d, J=7.3 Hz, 1H), 8.11-8.04 (m, 1H), 7.71 (d, J=16.0 Hz, 1H), 7.41 (dd, J=7.3, 1.6 Hz, 1H), 6.84 (d, J=16.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 1.27 (t, J=7.1 Hz, 3H).

Intermediate 104: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Thionyl chloride (0.17 mL, 2.3 mmol) was added to a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 25, 480 mg, 1.14 mmol) and 2 drops of DMF in DCM (6 mL). The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure, to provide the title compound which was used without further purification. MS (ESI): mass calcd. for C₂₁H₂₁ClF₃N₃O₂, 439.1; m/z found, 440.2 [M+H]⁺.

Intermediate 105: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 1M Aqueous potassium hydroxide (2.2 mL, 2.2 mmol) was added to a mixture of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (Intermediate 20, 1.89 g, 6.50 mmol), ethyl (E)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (Intermediate 103, 501 mg, 2.17 mmol), and [Rh(COD)Cl]₂ (107.8 mg, 0.219 mmol) in 1,4-dioxane (7.5 mL). The reaction was heated at 110° C. overnight. After this time, the reaction mixture was cooled to room temperature, filtered, and concentrated. The residue was diluted in water, ethyl acetate, and brine. The resulting biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (360 mg, 42% yield). MS (ESI): mass calcd. for C₂₂H₂₅N₃O₄, 395.2; m/z found, 396.1 [M+H]⁺.

Step B: Ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A mixture of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (360 mg, 0.91 mmol) and potassium carbonate (260 mg, 1.88 mmol) in ethanol (9 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, then dissolved in water and DCM. The resulting biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound which was used without further purification (259 mg, 80% yield). MS (ESI): mass calcd. for C₂₀H₂₃N₃O₃, 353.2; m/z found, 354.3 [M+H]⁺.

Step C: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (260 mg, 95% yield) was prepared using analogous conditions as described in Intermediate 104 where ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 25). MS (ESI): mass calcd. for C₂₀H₂₂ClN₃O₂, 371.1; m/z found, 372.1 [M+H]⁺.

Intermediate 106: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: 4-Bromo-2-hydrazinyl-3-methylpyridine. 4-Bromo-2-fluoro-3-methylpyridine (100 g, 526 mmol), pyridine (1000 mL), and hydrazine hydrate (300 mL) were combined under an atmosphere of nitrogen stirred for 4 hours at 75° C. The resulting mixture was concentrated under vacuum, then diluted with 2000 mL of H₂O and stirred for 30 minutes. The solids were collected by filtration and washed with H₂O to provide the title compound which was used without further purification (90 g, 85% yield).

Step B: 7-Bromo-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. 4-Bromo-2-hydrazinyl-3-methylpyridine (25 g, 124 mmol), DCM (250 mL), and cyclopropanecarbaldehyde (9.96 g, 142 mmol) were combined under an atmosphere of nitrogen and stirred for 30 minutes at room temperature. This was followed by the addition of iodobenzene diacetate (47.8 g, 148 mmol), in portions at 0° C. The resulting solution was stirred for 12 hours at room temperature. The reaction was then quenched by the addition of 300 mL of water. The reaction mixture was partitioned between DCM and water. The resulting biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, washed with water, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound which was re-crystallized from DCM/hexane in the ratio of 1:3 to provide an orange solid (20 g, 65% yield). MS (ESI): mass calcd. for C₂₀H₁₀BrN₃, 251.0; m/z found, 252.0 M+H]⁺.

Step C: Ethyl (E)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. Anhydrous DMF (7 mL) was added to a mixture of 7-bromo-3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (1.25 g, 4.96 mmol) and Pd(OAc)₂ (96 mg, 0.43 mmol) under an atmosphere of nitrogen. Ethyl acrylate (2.3 mL, 21 mmol) and triethylamine (0.59 mL mg, 4.2 mmol) were added and the mixture was heated at 110° C. overnight. After this time, the reaction was cooled to room temperature, then filtered through a pad of diatomaceous earth, rinsing with ethyl acetate. The filtrate was collected, washed with water and brine, then dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-5% MeOH/DCM) to afford the title compound (140 mg, 24% yield). MS (ESI): mass calcd. for C₁₅H₁₇N₃O₂ 271.1; m/z found, 272.0 [M+H]⁺.

Step D: Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (149 mg, 54% yield) was prepared using analogous conditions as described in Intermediate 105, Step A where ethyl (E)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate was used instead of ethyl (E)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. MS (ESI): mass calcd. for C₂₅H₂₉N₃O₄, 435.2; m/z found, 436.0 [M+H]⁺.

Step E: Ethyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. The title compound (193 mg, 93% yield) was prepared using analogous conditions as described in Intermediate 105, Step B where ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₂₃H₂₇N₃O₃, 393.2; m/z found, 394.0 [M+H]⁺.

Step F: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (186 mg, 92% yield) was prepared using analogous conditions as described in Intermediate 104 where ethyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate was used instead of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 25). MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₂, 411.2; m/z found, 412.0 [M+H]⁺.

Intermediate 107: Ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate

The title compound (53.2 mg, 118% yield) was prepared using analogous conditions as described in Intermediate 105, Step B where ethyl 3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 90) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and the reaction was heated to 50° C. instead of performing the reaction at room temperature. MS (ESI): mass calcd. for C₂₂H₂₆N₄O₃, 394.2; m/z found, 395.2 [M+H]⁺.

Intermediate 108: (R/S)-Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate

Step A: (E)-Ethyl 3-(6-(acetoxymethyl)-5-m ethylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (E)-Ethyl 3-(6-(acetoxymethyl)-5-m ethylpyridin-2-yl)acrylate (Intermediate 15, 3.5 g, 13 mmol), 5-bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 16, 4.1 g, 17 mmol), DIPEA (5.2 g, 40 mmol), and 1,4-dioxane (30 mL) were added to a 100 mL round-bottomed flask. The mixture was sparged with N₂ for 5 minutes and then treated with Pd(t-Bu₃P)₂ (680 mg, 1.33 mmol). The resultant mixture was stirred and heated to 80° C. for 16 hours under N₂ before cooling to room temperature, pouring it into water (100 mL), and extracting with ethyl acetate (60 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether: ethyl acetate, 20:1 to 1:1, gradient elution) to afford the title compound (3.9 g, 68%) as a yellow oil. MS (ESI): mass calcd. for C₂₃H₂₆N₄O₄ 422.20, m/z found 423.1 [M+H]⁺.

Step B: (E)-Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)acrylate. (E)-Ethyl 3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (3.9 g, 9.2 mmol), K₂CO₃ (3.83 g, 27.7 mmol), EtOH (30 mL), and THF (10 mL) were added to a 100 mL round-bottomed flask. The resultant mixture was stirred at room temperature for 3 hours before pouring it into H₂O (100 mL) and extracting with ethyl acetate (80 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title product (3.6 g, 88%) as an oil. MS (ESI): mass calcd. for C₂₁H₂₄N₄O₃ 380.18, m/z found 381.1 [M+H]⁺.

Step C: (R/S)-Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate. Raney Ni (3.0 g) was added to a solution of (E)-ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)acrylate (3.6 g, 9.5 mmol) and ethyl acetate (30 mL). The resultant mixture was stirred under H₂ atmosphere (50 psi) at room temperature for 36 hours. The suspension was filtered through a pad of diatomaceous earth and the pad washed with ethyl acetate (100 mL). The filtrate was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC using a Phenomenex Synergi Max-RP, 250×50 mm×10 μm column (eluent: 5% to 55% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to afford the title compound (2.12 g). MS (ESI): mass calcd. for C₂₁H₂₆N₄O₃ 382.20, m/z found 383.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J=8.8 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 5.00-4.89 (m, 2H), 4.62 (q, J=7.3 Hz, 2H), 4.53 (d, J=5.1 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.39-3.32 (m, 1H), 3.06-2.97 (m, 1H), 2.79 (s, 3H), 2.18 (s, 3H), 1.42 (t, J=7.3 Hz, 3H), 1.01 (t, J=7.1 Hz, 3H).

Intermediate 109: 4-Bromo-2-hydrazinylpyridine

A mixture containing 4-bromo-2-fluoropyridine (50 g, 280 mmol) and hydrazine hydrate (414 mL, 8.54 mol) was heated to 50° C. After 16 hours, the suspension was cooled to room temperature, filtered, and the solids were washed with water. The washed solids were dried under reduced pressure to afford the title compound (50.5 g, 95%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, J=5.4 Hz, 1H), 7.70 (br s, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.67 (dd, J=1.7, 5.4 Hz, 1H).

Intermediate 110: 7-Bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine

TFAA (758 mL, 5.38 mol) was added dropwise to the stirring solid 4-bromo-2-hydrazinylpyridine (Intermediate 109, 50.5 g, 269 mmol). The resulting mixture was stirred at 50° C. After 16 hours, the mixture was poured slowly into water (200 mL) and then brought to pH 7-8 by addition of aqueous NaOH. The resulting suspension was filtered, and the filter cake was washed with water and then dried under reduced pressure to afford the title compound (62.8 g, 88%) as a white solid. MS (ESI): mass calcd. for C₇H₃BrF₃N₃, 264.9; m/z found, 267.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.58 (d, J=7.3 Hz, 1H), 8.48 (d, J=7.0 Hz, 1H), 7.40 (dd, J=1.7, 7.3 Hz, 1H).

Intermediate 111: 7-Bromo-3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine

The title compound (3.05 g) was prepared using analogous conditions as described in Intermediate 24 using propionic acid instead of TFAA. MS (ESI): mass calcd. for C₉H₁₀BrN₃, 239.0; m/z found, 240.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=7.2 Hz, 1H), 6.95 (d, J=7.3 Hz, 1H), 3.12-3.03 (m, 2H), 2.72 (s, 3H), 1.52-1.45 (m, 3H).

Intermediate 112: Ethyl (E)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate

A mixture of 7-bromo-3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 111, 1.05 g, 4.37 mmol), ethyl acrylate (2.1 mL, 19.4 mmol), triethylamine (1.6 mL, 11.5 mmol), and Pd(OAc)₂ (338 mg, 1.51 mmol) in DMA (12 mL) was degassed by bubbling nitrogen through the mixture. The mixture was then heated at 125° C. After 18 hours, the mixture was cooled to room temperature, diluted with ethyl acetate, and then filtered through diatomaceous earth. The filtrate was partitioned between ethyl acetate and water. The layers were separated. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, and then absorbed onto diatomaceous earth for purification by flash column chromatography (hexanes-ethyl acetate) to provide the title compound (494 mg, 44%). MS (ESI): mass calcd. for C₁₄H₁₇N₃O₂, 259.1; m/z found, 260.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=7.3 Hz, 1H), 7.89 (d, J=15.9 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 6.78 (d, J=15.8 Hz, 1H), 4.28-4.19 (m, 2H), 3.14-3.04 (m, 2H), 2.66 (s, 3H), 1.39-1.31 (m, 3H), 1.31-1.25 (m, 3H).

Intermediate 113: (*S)-7,7a,8,9-Tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

Step A: tert-Butyl 2-(((2-chloropyridine)-3-sulfonamido)methyl)azetidine-1-carboxylate. tert-Butyl (azetidin-2-ylmethyl)carbamate (9.2 g, 49.5 mmol) and potassium carbonate (7.8 g, 56.6 mmol) were suspended in a mixture of THF (100 mL) and water (25 mL). After 5 minutes, 2-chloropyridine-3-sulfonyl chloride (10 g, 47.2 mmol) was added. After stirring overnight, the solvents were removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate and these extractions resulted in several organic fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (17.9 g, 89%). This material was used in the next step without further purification. MS (ESI): mass calcd. for C₁₄H₂₀ClN₃O₄S, 361.1; m/z found, 261.7 [M-CO₂t-Bu]⁻.

Step B: N-(Azetidin-2-ylmethyl)-2-chloropyridine-3-sulfonamide. TFA (17.4 mL, 251 mmol) was added to a solution of tert-butyl 2-(((2-chloropyridine)-3-sulfonamido)methyl)azetidine-1-carboxylate (17.9 g, 41.9 mmol) in DCM (80 mL) which had been cooled to 0° C. The mixture was allowed to warm to room temperature. After 15 hours, TLC analysis indicated complete consumption of starting material and then the reaction mixture was concentrated to afford the title compound as a yellow oil (10.5 g, 96%). This material was used in the next step without further purification.

Step C: (*S)-7,7a,8,9-Tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. Cs₂CO₃ (38.5 g, 118 mmol) was added to a solution of N-(azetidin-2-ylmethyl)-2-chloropyridine-3-sulfonamide (10.3 g, 39.4 mmol) in DMSO (150 mL). The mixture was heated at 130° C. After 2 hours, the mixture was cooled to room temperature and then poured onto water. The aqueous layer was extracted with ethyl acetate and these extractions resulted in several organic fractions which were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound as a white solid (4.35 g, 49%). MS (ESI): mass calcd. for C₉H₁₁N₃O₂S, 449.2; m/z found, 226.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (dd, J=1.8, 4.9 Hz, 1H), 7.97 (dd, J=1.7, 7.6 Hz, 1H), 7.71 (br s, 1H), 6.95 (dd, J=4.9, 7.7 Hz, 1H), 4.16-4.06 (m, 1H), 4.04-3.93 (m, 1H), 3.67-3.56 (m, 1H), 3.34-3.26 (m, 2H), 2.31-2.19 (m, 1H), 2.18-2.09 (m, 1H). The mixture of 7,7a,8,9-Tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide isomers were separated by chiral SFC (stationary phase: Chiralpak AS-H 5 μm 250×20 mm, mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting enantiomer (2.05 g) was designated (*S). MS (ESI): mass calcd. for C₉H₁₁N₃O₂S, 449.2; m/z found, 226.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.30 (m, 1H), 7.99-7.93 (m, 1H), 7.69 (s, 1H), 6.97-6.91 (m, 1H), 4.15-4.07 (m, 1H), 4.04-3.94 (m, 1H), 3.65-3.57 (m, 1H), 3.41-3.26 (m, 2H), 2.30-2.19 (m, 1H), 2.19-2.09 (m, 1H). \

Intermediate 114: (*R)-7,7a, 8,9-Tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (2.09 g) from the chiral separation described in Intermediate 113 was designated (*R). MS (ESI): mass calcd. for C₉H₁₁N₃O₂S, 449.2; m/z found, 226.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.30 (m, 1H), 7.96 (dd, J=7.6, 1.7 Hz, 1H), 7.69 (s, 1H), 6.94 (dd, J=7.7, 4.8 Hz, 1H), 4.14-4.06 (m, 1H), 4.04-3.94 (m, 1H), 3.66-3.57 (m, 1H), 3.42-3.26 (m, 2H), 2.30-2.18 (m, 1H), 2.18-2.09 (m, 1H).

Intermediate 115: Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate

Step A: Ethyl (E)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. A mixture of ethyl (E)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)acrylate (Intermediate 15, 3.5 g, 13 mmol), 5-bromo-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 16, 4.1 g, 17 mmol), DIPEA (5.2 g, 40 mmol), and 1,4-dioxane (30 mL) was degassed by bubbling nitrogen gas through the mixture. After 5 minutes, Pd(t-Bu₃P)₂ (680 mg, 1.3 mmol) was added and then the resulting mixture was heated at 80° C. After 16 hours, the mixture was cooled to room temperature and then poured onto water. The aqueous was extracted with ethyl acetate and these extractions resulted in several organic fractions which were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound as a yellow oil (3.9 g, 68%). MS (ESI): mass calcd. for C₂₃H₂₆N₄O₄, 422.2; m/z found, 423.1 [M+H]⁺.

Step B: Ethyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)acrylate. A mixture of ethyl (E)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (3.9 g, 9.2 mmol), K₂CO₃ (3.8 g, 28 mmol), EtOH (30 mL), and THF (10 mL) was stirred at room temperature. After 3 hours, the mixture was poured onto water. The aqueous portion was extracted with ethyl acetate and these extractions resulted in several organic fractions which were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound as an oil (3.6 g, 88%). MS (ESI): mass calcd. for C₂₁H₂₄N₄O₃, 380.2; m/z found, 381.1 [M+H]⁺.

Step C: Ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate. A mixture of ethyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)acrylate (3.6 g, 9.5 mmol) and Raney nickel (3 g) in ethyl acetate (30 mL) was stirred under an atmosphere of hydrogen gas at room temperature. After 36 hours, the suspension was filtered through diatomaceous earth and the filtrate was concentrated to dryness to afford the title compound (3.5 g) which was combined with a second batch of the title compound which had been prepared in an analogous manner (2 g). The 5.5 g of the title compound was purified by preparative HPLC (Phenomenex Synergi Max-RP, 250×50 mm×10 μm column (eluent: 5% to 55% (v/v) CH₃CN and H₂O with 0.225% formic acid) to afford pure product (3.3 g). MS (ESI): mass calcd. for C₂₁H₂₆N₄O₃, 382.2; m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J=8.8 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 5.00-4.89 (m, 2H), 4.62 (q, J=7.3 Hz, 2H), 4.53 (d, J=5.1 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.39-3.32 (m, 1H), 3.06-2.97 (m, 1H), 2.79 (s, 3H), 2.18 (s, 3H), 1.42 (t, J=7.3 Hz, 3H), 1.01 (t, J=7.1 Hz, 3H).

Intermediate 116: (*R)-7,7a,8,9,10,11-Hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (2.16 g) from the chiral separation described in Intermediate 76 was designated (*R): ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.67 (m, 1H), 7.61-7.57 (m, 1H), 7.43-7.34 (m, 1H), 7.19-7.13 (m, 1H), 7.03-6.95 (m, 1H), 3.79-3.67 (m, 1H), 3.55-3.33 (m, 3H), 3.08-2.98 (m, 1H), 1.75-1.50 (m, 6H).

Intermediate 117: (*R)-3-Methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide

The second eluting isomer (289 mg) from the chiral separation described in Intermediate 77 was designated (*R): MS (ESI): mass calcd. for C₁₂H₁₇N₃O₂S, 267.1; m/z found, 268.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 8.07-8.00 (m, 1H), 7.71 (s, 1H), 4.20-4.09 (m, 2H), 3.49-3.39 (m, 1H), 3.34-3.25 (m, 1H), 3.21-3.13 (m, 1H), 2.20 (s, 3H), 1.74-1.52 (m, 6H).

Intermediate 118: 5-Bromo-1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole

The title compound (84 g) was prepared using analogous conditions as described in Intermediate 16 using cyclopropylmethanamine instead of ethylamine in Step A, DMF instead of acetic acid as solvent in Step B, SnCl₂.2H₂O instead of iron in Step C, acetonitrile/water instead of acetic acid/water in Step D, and 4-methylbenzenesulfonic acid hydrate as an additive in Step D. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76-7.72 (m, 1H), 7.70-7.65 (m, 1H), 4.59 (d, J=7.3 Hz, 2H), 2.71 (s, 3H), 1.40-1.28 (m, 1H), 0.56-0.49 (m, 2H), 0.48-0.42 (m, 2H).

Intermediate 119: 1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde

The title compound (34.3 g) was prepared using analogous conditions as described in Intermediate 28 using 5-bromo-1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 118) instead of 7-bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridine, triethylamine instead of K₃PO₄ as base, and ethanol instead of dioxane/water as solvent in Step A. MS (ESI): mass calcd. for C₁₂H₁₃N₃O, 215.1; m/z found, 216.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 4.62 (d, J=6.8 Hz, 2H), 3.05 (s, 3H), 1.43-1.32 (m, 1H), 0.58-0.52 (m, 2H), 0.51-0.45 (m, 2H).

Intermediate 120: 6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpyridine

Step A. (6-Bromo-3-methylpyridin-2-yl)methanol. This reaction was run in two batches starting with 30 g of 6-bromo-3-methylpicolinic acid for each batch. Borane tetrahydrofuran complex (1 M in THF, 280 mL, 280 mmol) was added dropwise to a solution of 6-bromo-3-methylpicolinic acid (30 g, 139 mmol) in THF (100 mL) at 0° C. The mixture was then heated at 50° C. After 16 hours, the reaction mixture was cooled to 0° C. and water (500 mL) was added slowly until gas evolution ceased. This mixture was stirred for 1 hour with warming to room temperature. At this point the two batches where combined. The combined mixture was extracted with ethyl acetate which resulted in several organic fractions. These fractions were combined, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford the title compound as a colorless oil (50 g). ¹H NMR (400 MHz, DMSO-d₆) δ 7.54 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 4.50 (s, 2H), 2.29 (s, 3H).

Step B: 6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpyridine. TBSCl (56 g, 372 mmol) was added to an ice-cooled solution of (6-bromo-3-methylpyridin-2-yl)methanol (50 g, 247 mmol) and imidazole (37.2 g, 546 mmol) in DCM (500 mL). The mixture was allowed to warm to room temperature over the course of 2 hours which resulted in a suspension being formed. The solids where removed by filtration through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography (eluent: petroleum etherethyl acetate) to afford the title compound as a colorless oil (30 g, 37%).

Intermediate 121: ((1-(tert-Butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane

Step A: tert-Butyl isobutyrate. A solution of tert-butanol (19 mL, 200 mmol) in DCM (40 mL) was added dropwise over five minutes to a solution of isobutyryl chloride (20 mL, 190 mmol) in DCM (90 mL). Triethylamine (40 mL, 290 mmol) was then added dropwise, slowly. Additional DCM (40 mL) was added followed by the addition of DMAP (1.1 g, 10 mmol). After 18 hours, 1 M aqueous HCl solution was added until the mixture was biphasic and each layer was homogeneous. The layers were separated and the aqueous portion was extracted with DCM. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by distillation (bath temperature of 125° C. and head temperature of 85-90° C. with ice-water cooling of the collection flask) to provide the title compound as a clear, colorless liquid (18.3 g, 67%). ¹H NMR (400 MHz, CDCl₃) δ 2.42 (dt, J=13.9, 7.0 Hz, 1H), 1.43 (s, 9H), 1.12 (s, 3H), 1.11 (s, 3H).

Step B: ((1-(tert-Butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane. A 1.6 M solution of n-butyllithium in hexanes (20.5 mL, 32.8 mmol) was added to a solution of diisopropylamine (5 mL, 35.7 mmol) in THF (25 mL) which had been cooled to 0° C. After 10 minutes, a solution of tert-butyl isobutyrate (4.3 g, 30 mmol) in THE (10 mL) was added dropwise. After 30 minutes, chlorotrimethylsilane (4.5 mL, 35.5 mmol) was added. The reaction flask was removed from the cooling bath and allowed to warm to room temperature. After 1.5 hours, the mixture was poured into a solution of ice water and hexanes. The layers were separated. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a light-yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.38 (s, 3H), 1.35 (s, 3H), 1.10 (s, 9H), 0.01 (s, 9H).

Intermediate 122: Methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: 3-(Trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine. To vial equipped with a stir bar was added 3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine, (Intermediate 110, 8.98 g, 33.8 mmol), potassium vinyltrifluoroborate (9.63 g, 71.9 mmol), potassium phosphate (31.1 g, 144 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (1.41 g, 1.71 mmol), 1,4-dioxane (88 mL) and distilled water (16 mL). The solution was degassed by bubbling nitrogen gas through it for 10 minutes, the vial was then capped and placed in a sand bath which had been heated at 100° C. After 1 hour, the vial was removed from the hot sand and allowed to cool to room temperature. The mixture was partitioned between ether and brine. The layers were separated and the organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: hexanes/ethyl acetate) to afford the title compound (5.74 g, 80%). MS (ESI): mass calcd. for C₉H₆F₃N₃, 213.1; m/z found, 214.1 [M+H]⁺.

Step B: 3-(Trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. To a solution of 3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (5.72 g, 26.8 mmol) in 1,4-dioxane (120 mL) and distilled water (40 mL) under positive pressure of nitrogen at room temperature, was added osmium tetroxide (2.5 wt. % in tert-butanol solution, 14 mL, 1.38 mmol) followed immediately by addition of sodium periodate (17 mL, 81.4 mmol) resulting in the formation of a white ppt. After stirring for 18 hours, the reaction mixture was cooled to room temperature and partitioned between ether and water. Brine was added and the aqueous was extracted three times with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: hexanes/ethyl acetate) to afford a white foam. The foam was dissolved with minimal DCM and then hexanes were added until a white solid crashed out of solution. The white solids were isolated by vacuum filtration to afford the title compound (3.23 g, 56%). MS (ESI): mass calcd. for C₈H₄F₃N₃O, 215.1; m/z found, 216.1 [M+H]⁺.

Step C: 5-(Hydroxy(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate. To an oven-dried flask fitted with a reflux condenser and an argon gas inlet was added 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. (1.7 g, 8 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylpivalate (Intermediate 42, 3.1 g, 9.3 mmol), potassium carbonate (3.6 g, 26 mmol), palladium chloride (106 mg, 0.598 mmol), tri(1-naphthyl)phosphine (169 mg, 0.397 mmol) and THF (86 mL). The reaction was heated in a sand bath set at 75° C. After 17 hours, the reaction mixture was allowed to cool to room temperature and additional 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylpivalate, potassium carbonate, palladium chloride, and tri(1-naphthyl)phosphine were added. The reaction was heated in a sand bath set at 75° C. After 6 hours, the reaction was cooled to room temperature and the mixture was partitioned between ether and water. The layers were separated. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (hexanes to ethyl acetate) to afford the title compound (2.5 g, 75%). MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.1 [M+H]⁺.

Step D: 5-(Chloro(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate. To a vial under a positive pressure of nitrogen, was added 5-(hydroxy(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate (1.35 g, 3.20 mmol) and DCM (39 mL) followed by thionyl chloride (0.20 mL, 2.73 mmol). After 20 minutes, the mixture was partitioned between DCM and distilled water. The pH of the aqueous layer was adjusted to pH 7 by the addition of saturated aqueous NaHCO₃. The layers were separated. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (1.40 g, 99%). MS (ESI): mass calcd. for C₂₁H₂₁ClF₃N₃O₂, 439.1; m/z found, 440.1 [M+H]⁺.

Step E: Methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. To a flask under argon, was added 5-(chloro(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate (1.40 g, 3.18 mmol), DCM (82 mL), dimethyl ketene methyl trimethylsilyl acetal (0.970 mL, 4.77 mmol) and indium (III) bromide (228 mg, 0.637 mmol). After 18 hours, an additional equivalent of each dimethyl ketene methyl trimethylsilyl acetal and indium (III) bromide was added. After 4 days, the mixture was partitioned between hexanes DCM (1:1) and saturated aqueous NaHCO₃. The layers were separated. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The bright orange residue was purified by flash column chromatography (hexanes to ethyl acetate) to afford the title compound (438 mg, 27%) as a light orange foam. MS (ESI): mass calcd. for C₂₆H₃₀F₃N₃O₄, 505.2; m/z found, 506.5 [M+H]⁺.

Intermediate 123: 3-(3-(Benzyloxy)propoxy)propan-1-ol

Step A: 3-(Benzyloxy) propyl-4-methylbenzenesulfonate. 3-(Benzyloxy)propan-1-ol (10.0 g, 60.2 mmol), p-toluenesulfonyl chloride (17.2 g, 90.2 mmol), triethylamine (25.0 mL, 179 mmol), and dichloromethane (100 mL) were stirred at 20° C. for 3 hours before pouring into water (50 mL) and extracting with dichloromethane (2×). These extractions resulted in several organic fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether:ethyl acetate=1:0 to 5:1, gradient elution) to afford the title compound (18 g) as a brown oil, which was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=8.4 Hz, 2H), 7.38-7.22 (m, 7H), 4.40 (s, 2H), 4.19-4.14 (m, 2H), 3.50 (t, J=6.0 Hz, 2H), 2.42 (s, 3H), 1.98-1.90 (m, 2H).

Step B: 3-(3-(benzyloxy)propoxy)propan-1-ol. Sodium hydride in mineral oil (6.0 g, 60% purity, 0.15 mmol) was added in portions to a solution of propane-1,3-diol (17.0 g, 223 mmol) and DMF (40 mL) at 0° C. The resulting mixture was stirred for 2 hours with gradual warming to room-temperature. The reaction mixture was again cooled to 0° C. and then a solution of 3-(benzyloxy)propyl 4-methylbenzenesulfonate (18.0 g) and DMF (40 mL) was added. This mixture was stirred while heating at 80° C. for 12 hours before cooling to room temperature, pouring into aqueous saturated NH₄Cl (40 mL) solution, and extracting with ethyl acetate (2×). These extractions resulted in several organic fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether:ethyl acetate=1:0 to 1:1, gradient elution) to afford the title compound (9.0 g, 71%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.25 (m, 4H), 4.49 (s, 2H), 3.78-3.71 (m, 2H), 3.71-3.66 (m, 1H), 3.59 (t, J=5.6 Hz, 2H), 3.54 (t, J=6.4 Hz, 4H), 2.05 (s, 2H), 1.92-1.82 (m, 4H).

Intermediate 124: 7′-Bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3 [1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 6-Bromo-2-chloropyridine-3-sulfonyl chloride. HBF₄ (32.0 mL, 206 mmol) was added drop-wise to a solution of 6-bromo-2-chloropyridin-3-amine (30.0 g, 145 mmol) and acetonitrile (150 mL) which had been cooled to 0° C. The resulting mixture was stirred at 0° C. for 10 minutes before adding tert-butyl nitrite (26.0 mL, 219 mmol) drop-wise. The resulting mixture was stirred at 0° C. for 1 hour which resulted in the preparation of a 6-bromo-2-chloropyridine-3-diazonium tetrafluoroborate solution. In a separate 1 L three-necked round-bottomed flask was added copper(I) chloride (22.0 g, 222 mmol) and acetic acid (120 mL). This mixture was cooled to 0° C., SO₂ gas (>1.3 M) bubbled through it at 0° C. for 1 hour to prepare a sulfur solution. At this time, the above 6-bromo-2-chloropyridine-3-diazonium tetrafluoroborate solution, which had also been cooled to 0° C., was added drop-wise to the sulfur solution which had been cooled to 0° C. The resulting mixture was stirred for 12 hours with gradual warming to room temperature. The suspension was filtered through a pad of diatomaceous earth and the pad washed with ethyl acetate (100 mL). The filtrate was quenched with aqueous saturated NaHCO₃ (200 mL) solution, stirred for 20 minutes, and then extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with water (2×) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 10:1, gradient elution) to afford the title compound (24 g), which was used in the next step without further purification.

Step B: 6-Bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide. A solution of 6-bromo-2-chloropyridine-3-sulfonyl chloride (48 g) and THF (100 mL) was added drop-wise to a mixture of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (20.0 g, 152 mmol), K₂CO₃ (65.0 g, 470 mmol), THF (100 mL), and H₂O (50 mL). The resulting mixture was stirred for 12 hours with gradual warming to room temperature before concentrating to dryness under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 1:1, gradient elution) to afford the title compound (35 g), which was used in the next step without further purification.

Step C: 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. t-BuOK (5.5 g, 49 mmoL) was added in portions to a solution of 6-bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide (10 g) and DMSO (40 mL) which had been cooled to 0° C. This mixture was then heated at 100° C. for 2 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (50 mL) and the pH of the solution was adjusted to pH=6 with 1 N HCl (20 mL) which resulted in the formation of a suspension. The solid of the suspension was isolated via filtration and the filter cake washed with petroleum ether (20 mL) before drying under reduced pressure to give the product (7.0 g), which was combined with another batch of 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (14 g) to afford 21 g of product to be purified. The 21 g of product was then triturated with ethyl acetate (30 mL) and the solids were isolated via filtration. The filter cake was washed with petroleum ether/ethyl acetate (10:1, 50 mL) before drying under reduced pressure to afford the title compound (18.5 g) as a gray solid. MS (ESI): mass calcd. for C₁₁H₁₃BrN₂O₄S 348.0, m/z found 349.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54-8.47 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 3.76-3.66 (m, 2H), 3.62-3.55 (m, 2H), 3.49 (d, J=6.4 Hz, 2H), 1.68-1.53 (m, 4H).

Intermediate 125: 7′-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

To a solution of (4,4-difluoropiperidin-1-yl)ethan-1-ol (655 mg, 3.97 mmol) in toluene (5.0 mL) under N₂ which had been cooled to 0° C. was added NaH (164 mg, 60% dispersion in oil, 4.1 mmol) in two batches. After stirring at 0° C. for 10 minutes, the reaction was warmed to room temperature and the mixture stirred an additional 50 minutes. This solution was then transferred via syringe to a 48 mL screw-capped pressure vessel under N₂ containing 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (500 mg, 1.32 mmol, Intermediate 124), tris(dibenzylidienaceton)dipalladium(0) (121 mg, 0.13 mmol) and [1,1′-binaphthalen]-2-yl-di-tert-butylphosphine (105 mg, 0.26 mmol). The reaction was heated to 100° C. for 18 h. After that time, the reaction was allowed to cool to room temperature, and 0.15 mL of AcOH was added. The mixture was then diluted with ethyl acetate and filtered through a pad of diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by flash column chromatography (eluent: methanol/DCM, 0:1 to 1:10, gradient elution) to afford the title compound (202 mg, 35%). MS (ESI): mass calcd. for C₁₈H₂₅F₂N₃O₅S 433.1, m/z found 434.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.40 (t, J=5.8 Hz, 2H), 3.85-3.76 (m, 2H), 3.64 (d, J=11.3 Hz, 2H), 3.47 (s, 2H), 2.78 (t, J=5.8 Hz, 2H), 2.62 (t, J=5.7 Hz, 4H), 1.99-1.90 (m, 4H), 1.62 (d, J=4.3 Hz, 4H).

Intermediate 126: tert-Butyl 4-(2-((1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)oxy)ethyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (1020 mg, 4.4 mmol) in DMSO (6.0 mL) under N₂ was added sodium hydride (65 mg, 1.6 mmol) and the resulting mixture was allowed to stir at room temperature for 45 minutes. 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (300 mg, 0.98 mmol, Intermediate 68) was then added and the reaction stirred at room temperature for 18 h. The reaction was quenched with aqueous saturated NH₄Cl solution and extracted with ethyl acetate (4×). These extractions resulted in several organic fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: MeOH/DCM; 0:100 to 1:10, gradient elution) to afford the title compound (382 mg, 78%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.40 (t, J=5.8 Hz, 2H), 3.81 (ddd, J=13.1, 9.2, 4.2 Hz, 2H), 3.63 (dd, J=10.8, 3.9 Hz, 2H), 3.46 (s, 2H), 2.71 (t, J=5.8 Hz, 2H), 2.42 (t, J=5.1 Hz, 4H), 1.62 (t, J=4.4 Hz, 4H), 1.39 (s, 9H).

Intermediate 127: 7′-(2-(Piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

To a 48-mL screw capped pressure vessel under N₂ was added 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (400 mg, 1.5 mmol, Intermediate 67), 2-(piperidin-1-yl)ethan-1-ol (595 mg, 4.6 mmol), cesium carbonate (1.5 g, 4.6 mmol), Josiphos Pd(0) pre-catalyst G3 (142 mg, 0.15 mmol) and DMA (10 mL). The mixture was sparged with N₂ for 5 minutes and then heated to 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature and poured into a 50/50 mixture of brine/water and extracted with ethyl acetate. These extractions resulted in several organic fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue purified by flash column chromatography (eluent, MeOH/DCM; 0:100 to 3:20, gradient elution) to afford the title compound (240 mg, 44%). LC-MS (ESI): mass calcd. for C₁₆H₂₃N₃O₄S 353.1, m/z found 354.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=8.5 Hz, 1H), 6.52 (d, J=8.5 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H), 3.56 (s, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.47 (s, 4H), 1.59 (s, 4H), 1.43-1.34 (m, 2H), 1.17-1.10 (m, 2H), 0.71-0.66 (m, 2H).

Intermediate 128: tert-Butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

Step A: 8-Methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine. A mixture of 7-bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (60.0 g, 214 mmol, Intermediate 24), potassium trifluoro(vinyl)borate (57.0 g, 426 mmol), K₃PO₄ (136 g, 641 mmol), 1,4-dioxane (500 mL), and H₂O (100 mL) was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl₂ (9.4 g, 13 mmol). The resultant mixture was sparged with Ar again for another 5 minutes and then heated at 110° C. for 16 hours before cooling to room-temperature. The suspension was filtered, and the solids were washed with ethyl acetate (200 mL). The filtrate was poured into H₂O (500 mL), and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate; 10:1 to 1:1, gradient elution) to afford the title compound (42 g, 86%). MS (ESI): mass calcd. for C₁₀H₈F₃N₃ 227.1, m/z found 228.1 [M+H]⁺.

Step B: 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. K₂OsO₄.2H₂O (1.36 g, 3.69 mmol) was added to a solution of 8-methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (21 g, 92 mmol) 1,4-dioxane (700 mL) and H₂O (distilled, 700 mL). NaIO₄ (59 g, 276 mmol) was added and the resulting mixture stirred at room-temperature for 2 hours. The mixture was filtered, quenched with H₂O (600 mL) and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether:/ethyl acetate; 10:1 to 3:1, gradient elution) to afford the title compound. MS (ESI): mass calcd. for C₉H₆F₃N₃O 229.1, m/z found 230.1 [M+H]⁺.

Step C: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. i-PrMgCl.LiCl (80.6 mL, 1.3 M in THF, 105 mmol) was added drop-wise to a mixture of tert-butyl-((5-iodo-2-methylbenzyl)oxy)dimethylsilane (27.8 g, 76.7 mmol) and THF (200 mL) which had been cooled to −15° C. The reaction mixture was stirred at −15° C. for 1 hour followed by drop-wise addition of a solution of 8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (16 g, 70 mmol) in THF (100 mL). The reaction mixture was stirred for 2 hours with gradual warming to room-temperature before quenching with saturated NH₄Cl (500 mL) and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 20:1 to 2:1, gradient elution) to afford the title compound (24 g, 73%). MS (ESI): mass calcd. for C₂₃H₃₀F₃N₃O₂Si 465.2, m/z found 466.3 [M+H]⁺.

Step D: tert-Butyl 3-(34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 2,2,2-Trichloroacetonitrile (431 μL, 4.30 mmol) was added to a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (1.0 g, 2.1 mmol), DBU (64 μL, 0.43 mmol), and 1,2-dichloroethane (5 mL) under Na. After stirring for 1 hour at room-temperature ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (4.65 g, 21.5 mmol) and BF₃.Et₂O (0.24 mL, 1.9 mmol) were added and the reaction stirred for an additional 1.5 hours before quenching with H₂O (30 mL) and extracting with dichloromethane (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 20:1 to 5:1, gradient elution) to afford the title compound (380 mg, 27.9%). MS (ESI): mass calcd. for C₃₁H₄₄F₃N₃O₃Si 591.3, m/z found 592.3 [M+H]⁺.

Step E: tert-Butyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. TBAF (7.3 mL, 1 M in THF, 7.3 mmol) was added to a solution of tert-butyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (2.15 g, 3.63 mmol) and THF (20 mL). The resulting mixture was stirred at room-temperature for 2 hours before quenching with H₂O (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (3×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 1:1, gradient elution) to afford the title compound (1.3 g, 75%). MS (ESI): mass calcd. for C₂₅H₃₀F₃N₃O₃ 477.2, m/z found 478.2 [M+H]⁺.

Step F: tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The mixture of tert-butyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.3 g, 2.7 mmol) isomers were separated by chiral SFC (stationary phase: REGIS (s,s) WHELK-O1 250 mm×50 mm, 10 μm; eluent: 35% to 35% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The first eluting isomer (561 mg, 43%) was designated (*S). MS (ESI): mass calcd. for C₂₅H₃₀F₃N₃O₃ 477.2, m/z found 478.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=7.3 Hz, 1H), 7.32-7.26 (m, 2H), 7.12-7.08 (m, 1H), 7.07-7.04 (m, 1H), 5.04 (t, J=5.3 Hz, 1H), 4.72 (s, 1H), 4.43 (d, J=5.1 Hz, 2H), 2.65 (s, 3H), 2.17 (s, 3H), 1.29 (s, 3H), 1.21 (s, 3H), 1.17 (s, 9H).

Intermediate 129: tert-Butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

Step A: (5-Iodo-2-methylphenyl)methanol. Borane tetrahydrofuran complex (276 mL, 1 M in THF, 276 mmol) was added drop-wise to a solution of 5-iodo-2-methylbenzoic acid (60.0 g, 229 mmol) and THF (500 mL) that had been cooled to 0° C. The resulting mixture was stirred for 20 minutes at room temperature and then heated at 50° C. for 3 hours before cooling to 0° C. This mixture was treated with H₂O (250 mL) dropwise, stirred for another 1 hour with gradual warming to room temperature, and then extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (55 g, 97%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (s, 1H), 7.50-7.39 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 4.41 (s, 2H), 2.19-2.07 (m, 3H).

Step B: tert-Butyl((5-iodo-2-methylbenzyl)oxy)dimethylsilane. TB SCI (37.0 g, 245 mmol) was added to a solution of (5-iodo-2-methylphenyl)methanol (55.0 g, 222 mmol), imidazole (30.6 g, 449 mmol), and dichloromethane (600 mL) which had been cooled to 0° C. The resulting mixture was stirred for 16 hours with gradual warming to room-temperature. After such time, the reaction mixture was heated at 75° C. for 3 hours before cooling to room temperature. Solids that had formed during the above described procedure were isolated via filtration and the filtrate concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0, gradient elution) to afford the title compound (67 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (s, 1H), 7.41 (dd, J=7.9, 1.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.55 (s, 2H), 2.08 (s, 3H), 0.82 (s, 9H), 0.08 (s, 6H).

Step C: tert-Butyldimethyl((2-methyl-5-vinylbenzyl)oxy)silane. Pd(dppf)Cl₂ (5.5 g, 7.5 mmol) was added to a mixture of tert-butyl((5-iodo-2-methylbenzyl)oxy)dimethylsilane (67.0 g, 185 mmol), potassium trifluoro(vinyl)borate (50.0 g, 373 mmol), K₃PO₄ (119 g, 561 mmol), 1,4-dioxane (700 mL), and H₂O (140 mL) under Na. The mixture was stirred at 100° C. for 3 hours before cooling to room-temperature, pouring it into water (100 mL), and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 1:0, gradient elution) to afford the title compound (42.1 g, 87%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (s, 1H), 7.24 (dd, J=7.7, 1.6 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.69 (dd, J=17.6, 11.0 Hz, 1H), 5.72 (dd, J=17.6, 0.7 Hz, 1H), 5.21-5.16 (m, 1H), 4.67 (s, 2H), 2.22 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H).

Step D: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylbenzaldehyde. K₂OsO₄.2H₂O (2.91 g, 7.90 mmol) was added to a solution of tert-butyldimethyl((2-methyl-5-vinylbenzyl)oxy)silane (42.0 g, 158 mmol), 1,4-dioxane (500 mL), and H₂O (500 mL). The mixture was treated with NaIO₄ (102 g, 477 mmol) slowly and then stirred at room-temperature for 2 hours. The resulting suspension was isolated via filtration and the filter cake washed with ethyl acetate (3×). The aqueous layer was extracted with ethyl acetate (2×). These extractions resulted in several organic fractions that were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 10:1, gradient elution) to afford the title compound (34.7 g, 83%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 7.90 (s, 1H), 7.72 (dd, J=7.7, 1.6 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 4.75 (s, 2H), 2.32 (s, 3H), 0.92 (s, 9H), 0.10 (s, 6H).

Step E: 2-Hydrazinyl-4-iodo-3-methylpyridine. 2-Fluoro-4-iodo-3-methylpyridine (50.0 g, 211 mmol) was added to a 1 L round-bottomed flask containing hydrazine hydrate (345 mL, 7.11 mol). The resulting mixture was heated at 50° C. for 16 hours before cooling to the room temperature. The resulting suspension was isolated via filtration and the filter cake washed with water (3×) before drying under reduced pressure to afford the title compound (50.2 g, 96%).

Step F: 3-(Difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. 2,2,2-Trifluoroacetic anhydride (502 mL, 4.04 mmol) was added drop-wise to 2-hydrazinyl-4-iodo-3-methylpyridine (50.2 g, 202 mmol). The resulting mixture was heated at 75° C. for 32 hours before cooling to room-temperature. The pH of the solution was adjusted to pH 7-8 with 5 N aqueous NaOH solution. The resulting suspension was filtered, and the filter cake washed with water (3×) before drying under reduced pressure to afford the title compound (56.8 g, 79%). MS (ESI): mass calcd. for C₈H₆F₂IN₃309.0 m/z found 310.0 [M+1-1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (d, J=7.3 Hz, 1H), 7.86-7.58 (m, 1H), 7.45 (d, J=7.0 Hz, 1H), 2.64 (s, 3H).

Step G: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. i-PrMgCl.LiCl (33.5 mL, 1.3 M in THF, 43.6 mmol) was added drop-wise to a solution of 3-(difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (12.3 g, 39.8 mmol) and THF (150 mL) which had been cooled to −20° C. This mixture was stirred at −20° C. for 1 hour. At such time a solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylbenzaldehyde (9.6 g, 36 mmol) and THF (50 mL) was added dropwise. The resulting mixture was stirred for 16 hours with gradual warming to room-temperature before quenching with aqueous saturated NH₄Cl solution (50 mL), pouring into H₂O (30 mL), and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:1, gradient elution) to afford the title compound (5 g) which was used without further purification. MS (ESI): mass calcd. for C₂₃H₃₁F₂N₃O₂Si 447.2 m/z found 448.2 [M+H]⁺.

Step H: 7-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. SOCl₂ (3.6 mL, 50 mmol) was added dropwise to a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (27.3 g, 40.9 mmol), 2,6-di-tert-butylpyridine (23 mL), and dichloromethane (180 mL) which had been cooled to 0° C. The resulting mixture was stirred at 0° C. for 20 minutes before adjusting the pH with aqueous saturated NaHCO₃ solution to pH=7. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by FCC (eluent: petroleum ether/ethyl acetate, 10:1 to 5:1, gradient elution) to afford the title compound (18.5 g).

Step I: tert-Butyl 3-(34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. InBr₃ (3.06 g, 8.63 mmol) was added to a solution of 7-((3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (17.5 g, 37.6 mmol), ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (81.28 g, 375.6 mmol), and dichloromethane (200 mL) under Na. The resulting mixture was sparged with Na for another 5 minutes and then stirred at room temperature under Na for 3 days before quenching with H₂O (50 mL). The mixture was combined with another batch of tert-butyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate and the organic and aqueous portions were separated. The aqueous layer extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by FCC (eluent:petroleum ether/ethyl acetate, 10:1 to 3:1, gradient elution) to afford 23 g of the title compound. This material was further purified by preparative HPLC (stationary phase: YMC-Triart Prep C18, 150 mm×40 mm×7 μm column, eluent: 70% to 100% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to afford the title compound (7.6 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=7.3 Hz, 1H), 7.89-7.57 (m, 1H), 7.18-7.12 (m, 3H), 7.12-7.06 (m, 1H), 4.73 (s, 1H), 4.60 (s, 2H), 2.59 (s, 3H), 2.16 (s, 3H), 1.31 (s, 3H), 1.20 (d, J=2.0 Hz, 3H), 1.19-1.16 (m, 9H), 0.75 (s, 9H), −0.02-0.09 (m, 6H).

Step J: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. TBAF (28.3 mL, 1 M in THF, 28.3 mmol) was added to a solution of tert-butyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (8.1 g, 14 mmol) and THF (80 mL). The resulting mixture was stirred for 5 hours at room-temperature before pouring into water (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 2:3, gradient elution) to afford the title compound (5.4 g, 84%). MS (ESI): mass calcd. for C₂₅H₃₁F₂N₃O₃ 459.2 m/z found 460.3 [M+H]⁺.

Step K: (*S)-tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. The mixture of 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-4-(3-(morpholine-4-carbonyl)phenyl)benzofuran-2-yl)propanoic acid isomers were separated by chiral SFC (stationary phase: REGIS (s,s) WHELK-O1 250 mm×50 mm, 10 μm, eluent: 35% to 35% (v/v) supercritical CO₂ in IPA with 0.1% NH₃). The first eluting isomer (2.46 g, 37%) was designated (*S). MS (ESI): mass calcd. for C₂₅H₃₁F₂N₃O₃ 459.2 m/z found 460.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=7.6 Hz, 1H), 7.86-7.58 (m, 1H), 7.29-7.23 (m, 2H), 7.12-7.08 (m, 1H), 7.07-7.03 (m, 1H), 5.05 (t, J=5.4 Hz, 1H), 4.68 (s, 1H), 4.42 (d, J=5.4 Hz, 2H), 2.61 (s, 3H), 2.17 (s, 3H), 1.28 (s, 3H), 1.21 (s, 3H), 1.16 (s, 9H).

Intermediate 130: Ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

To a solution of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (1.5 g, 3.56 mmol, Intermediate 25) in THF (25 mL) was added (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-d][1,2,5]thiadiazepine 5,5-dioxide (1.3 g, 4.97 mmol) and triphenylphosphine (1.4 g, 5.34 mmol). After the reaction mixture was homogenous, diisopropyl azodicarboxylate (1.2 mL, 5.94 mmol) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was then poured into saturated bicarbonate and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in DCM and purified by flash column chromatography (eluent: EtOAc/Hexanes; 0:100 to 40:60, gradient elution) to afford the title compound (1450 mg, 62%). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S 656.2, m/z found 657.3 [M+H]⁺.

Intermediate 131: 7′-Chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2,6-Dichloro-5-methylpyridin-3-amine. NCS (32.9 g, 246 mmol) was added in portions to a solution of 2-chloro-5-methylpyridin-3-amine (35.0 g, 245 mmol) and acetonitrile (250 mL). The resulting mixture was heated at 35° C. for 16 hours before cooling to room temperature. The resulting suspension was filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 4:1, gradient elution) to afford the title compound (45 g, 99%). MS (ESI): mass calcd. For C₆H₆C₁₂N₂ 176.0 m/z found 176.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (s, 1H), 5.65 (br s, 2H), 2.53 (s, 3H).

Step B: 2,6-Dichloro-5-methylpyridine-3-sulfonyl chloride. HBF₄ (56.0 mL, 365 mmol) was added drop-wise to a solution of 2,6-dichloro-5-methylpyridin-3-amine (43.0 g, 243 mmol) and acetonitrile (300 mL) at which had been cooled to 0° C. This mixture was stirred at 0° C. for 10 minutes, treated with tert-butyl nitrite (44.0 mL, 370 mmol) drop-wise, followed by additional stirring at 0° C. for another 2 hours to prepare a 2,6-dichloro-5-methylpyridine-3-diazonium tetrafluoroborate solution. In a separate flask, copper(I) chloride (36.0 g, 364 mmol) and acetic acid (300 mL) were mixed and cooled to 0° C. This copper chloride/acetic acid was then treated with the above 2,6-dichloro-5-methylpyridine-3-diazonium tetrafluoroborate solution which had also been cooled to 0° C. The resulting mixture was stirred for 16 hours with gradual warming to room-temperature. The suspension was filtered through a pad of diatomaceous and the pad washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure and then purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 1:1, gradient elution) to afford the title compound (39.5 g) as a yellow oil, which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s, 1H), 2.28 (s, 3H).

Step C: 2,6-Dichloro-N-((l-hydroxycyclopropyl)methyl)-5-methylpyridine-3-sulfonamide. To a mixture of K₂CO₃ (28.7 g, 208 mmol), THF (100 mL) and H₂O (20 mL) which had been cooled to 0° C. was added 1-(aminomethyl)cyclopropanol (4.30 g, 49.4 mmol). The resulting mixture was stirred for 10 minutes at 0° C. and then treated with 2,6-dichloro-5-methylpyridine-3-sulfonyl chloride (18.0 g, 69.1 mmol). This mixture was stirred for 2 hours at 0° C. before concentrating to dryness under reduced pressure. The residue was poured into water and extracted with ethyl acetate (5×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 1:1, gradient elution) to afford the title compound (12 g, 49%). MS (ESI) mass calcd. for C₁₀H₁₂Cl₂N₂O₃S 310.0 m/z found 310.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.23-8.17 (m, 1H), 5.17 (s, 1H), 3.04-2.98 (m, 2H), 2.35 (s, 3H), 0.42 (s, 4H).

Step D: 7′-Chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. To a solution of 2,6-dichloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methylpyridine-3-sulfonamide (11.0 g, 35.3 mmol) and DMSO (80 mL) was added t-BuOK (10.0 g, 89.1 mmol). This mixture was heated at 90° C. for 16 hours before cooling to room-temperature, and concentrating to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 3:2, gradient elution). This product was further purified by reverse phase preparative HPLC (stationary phase: PREPL-M Xbridge BEH C18 250 mm×50 mm×10 μm column; eluent, CH₃CN/H₂O (with 0.04% NH₃ and 10 mM NH₄HCO₃) 10% to 43%, gradient elution) to afford the title product (2.3 g, 23%). MS (ESI) mass calcd. for C₁₀H₁₁ClN₂O₃S 274.0 m/z found 275.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.24 (s, 1H), 3.52 (br s, 2H), 2.37 (s, 3H), 0.97-0.91 (m, 2H), 0.82-0.76 (m, 2H).

Intermediate 132: 7′-Chloro-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (8.48 g, 63%) was prepared using analogous conditions as described in Intermediate 131 where 4-(aminomethyl)tetrahydro-2H-pyran-4-ol was used instead of 1-(aminomethyl)cyclopropan-1-ol in step C. MS (ESI): mass calcd. for C₁₂H₁₅ClN₂O₄S 318.0 m/z found 318.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 8.14 (s, 1H), 3.83-3.69 (m, 2H), 3.67-3.56 (m, 2H), 3.50 (s, 2H), 2.36 (s, 3H), 1.71-1.51 (m, 4H).

Intermediate 133: tert-Butyl 4-(2-((1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)oxy)ethyl)piperidine-1-carboxylate

The title compound (450 mg, 93%) was prepared using analogous conditions as described in Intermediate 126 where tert-butyl 4-(2-hydroxyethyl-piperidine)-1-carboxylate was used instead of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate and 7′-chloro-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 132) was used instead of 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate, 68). MS (ESI): mass calcd. for C₂₄H₃₇N₃O₇S 511.2, m/z found 412.1 [M+H-boc]⁺.

Intermediate 134: 8′-Methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (1405 mg, 51%) was prepared using analogous conditions as described in Intermediate 126 where 2-(pyrrolidin-1-yl)ethan-1-ol was used instead of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate and 7′-chloro-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 132) was used instead of 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 68). MS (ESI): mass calcd. for C₁₈H₂₇N₃O₅S 397.2, m/z found 398.2 [M+H]⁺.

Intermediate 135: tert-Butyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

The mixture of tert-Butyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.3 g, 2.7 mmol, Intermediate 128, step E) isomers were separated by chiral SFC (stationary phase: REGIS (s,s) WHELK-O1 250 mm×50 mm, 10 μm; eluent: 35% to 35% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The second eluting isomer (535 mg, 41%) was designated (*R). MS (ESI): mass calcd. for C₂₅H₃₀F₃N₃O₃ 477.2, m/z found 478.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=7.1 Hz, 1H), 7.33-7.26 (m, 2H), 7.12-7.07 (m, 1H), 7.07-7.04 (m, 1H), 5.03 (t, J=5.4 Hz, 1H), 4.72 (s, 1H), 4.43 (d, J=5.1 Hz, 2H), 2.65 (s, 3H), 2.17 (s, 3H), 1.29 (s, 3H), 1.21 (s, 3H), 1.17 (s, 9H).

Intermediate 136: 8′-Methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

The title compound (274 mg, 42%) was prepared using analogous conditions as described in Intermediate 127 where 7′-chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) was used instead of 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 67). MS (ESI): mass calcd. for C₁₇H₂₅N₃O₄S, 367.2; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=1.0 Hz, 1H), 4.98 (s, 1H), 4.44-4.33 (m, 2H), 3.55 (s, 2H), 2.75 (s, 2H), 2.52 (s, 4H), 2.08 (d, J=0.9 Hz, 3H), 1.65-1.53 (m, 4H), 1.45-1.35 (m, 2H), 1.17-1.08 (m, 2H), 0.71-0.61 (m, 2H).

Intermediate 137: 8′-Methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (512 mg, 41%) was prepared using analogous conditions as described in Intermediate 127 where 7′-chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) was used instead of 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 67) and 2-(pyrrolidine-1-yl)ethan-1-ol instead of 2-(piperidin-1-yl)ethan-1-ol. MS (ESI): mass calcd. for C₁₆H₂₃N₃O₄S, 353.1; m/z found, 354.2 [M+H]⁺.

Intermediate 138: 7′-(2-(4-Methoxypiperidine-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

The title compound (250 mg, 71%) was prepared using analogous conditions as described in Intermediate 127 where 7′-chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) was used instead of 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 67) and 2-(4-methoxypiperidin-1-yl)ethan-1-ol instead of 2-(piperidin-1-yl)ethan-1-ol. MS (ESI): mass calcd. for C₁₈H₂₇N₃O₅S, 397.2; m/z found, 398.2 [M+H]⁺.

Intermediate 139: Benzyl (*R)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

The title compound (2.48 g, 99%) was prepared using analogous conditions as described in Intermediate 71 where methyl (*R)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 141) was used instead of methyl (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in step A. MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃ 421.2 m/z found 422.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 8.43 (d, J=7.3 Hz, 1H), 7.35-7.25 (m, 2H), 7.15 (dd, J=7.9, 2.1 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 5.02 (s, 1H), 4.79 (s, 1H), 4.43 (s, 2H), 2.67 (s, 3H), 2.18 (s, 3H), 1.33-1.22 (m, 6H).

Intermediate 140: 8′-Methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 6-Bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methylpyridine-3-sulfonamide. K₂CO₃ (26.2 g, 189 mmol) was added in portions to a solution of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (14.0 g, 83.5 mmol) and THF: H₂O (230 mL, 4:1) which had been cooled to 0° C. The resulting mixture was stirred for 5 min at 0° C. and then 6-bromo-2-chloro-5-methylpyridine-3-sulfonyl chloride (23.1 g, 75.7 mmol) was added. This mixture was allowed to slowly warm to room temperature and stirred for 12 hours before pouring it into water (80 mL) and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (27.8 g, 83%). MS (ESI): mass calcd. for C₁₂H₁₆BrClN₂O₄S 399.7 m/z found 400.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (m, 1H), 8.05 (m, 1H), 4.39 (s, 1H), 3.57-3.51 (m, 4H), 2.89 (d, J=5.1 Hz, 2H), 2.40 (s, 3H), 1.55-1.45 (m, 2H), 1.33 (d, J=13.0 Hz, 2H).

Step B: 7′-Bromo-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. t-BuOK (7.91 g, 70.5 mmol) was added in portions to a solution of 6-bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide (14.1 g, 35.2 mmol) in DMSO (110 mL) which had been cooled to 0° C. This mixture was then heated at 100° C. for 2 hours before cooling to room temperature and concentrating to dryness under reduced pressure. The residue was diluted with H₂O (60 mL) and the pH adjusted with 1 N HCl (100 mL) to pH=6. The resulting suspension was isolated via filtration and the filter cake washed with petroleum ether (60 mL) before drying under reduced pressure to give the title compound (10.08 g). This solid was further purified by preparative HPLC (stationary phase: YMC Triart C18, 250 mm×50 mm×7 μm column; eluent: 10% to 40% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to afford the title compound (7.13 g, 56%). MS (ESI): mass calcd. for C₁₂H₁₅BrN₂O₄S 363.2 m/z found 363.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (m, 1H), 8.09 (m, 1H), 3.79-3.70 (m, 2H), 3.61 (d, J=11.2 Hz, 2H), 3.50 (s, 2H), 2.36 (s, 3H), 1.69-1.55 (m, 4H).

Step C: 8′-Methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. Cs₂CO₃ (6.72 g, 20.6 mmol) was added to a mixture of 7′-bromo-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (2.5 g, 6.9 mmol), 2-(piperidin-1-yl)ethanol (2.67 g, 20.7 mmol), JosiPhos pre-catalyst G3 (0.64 g, 0.70 mmol), and DMA (30 mL) under Na. This mixture was heated at 95° C. for 16 hours before quenching with H₂O and extracting with ethyl acetate (2×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 0:1, gradient elution) to afford the title compound (2.1 g, 69%). MS (ESI): mass calcd. for C₁₉H₂₉N₃O₅S 411.5 m/z found 412.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (m, 1H), 7.83 (m, 1H), 4.39 (t, J=6.1 Hz, 2H), 3.87-3.76 (m, 2H), 3.62 (d, J=11.0 Hz, 2H), 3.43 (s, 2H), 2.66 (t, J=6.1 Hz, 2H), 2.44 (s, 4H), 2.12 (s, 3H), 1.60 (s, 4H), 1.51-1.45 (m, 4H), 1.40-1.33 (m, 2H).

Intermediate 141: Methyl (*R)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

Step A: (5-Bromo-2-methylphenyl)methanol. Borane tetrahydrofuran complex (250 mL, 1 M in THF, 250 mmol) was added drop-wise to a solution of 5-bromo-2-methylbenzoic acid (45.0 g, 209 mmol) and THF (400 mL) which had been cooled to 0° C. The mixture was heated at 50° C. for 2 hours before allowing to cool to room-temperature. The mixture was then further cooled to 0° C. and quenched by slow addition of MeOH (250 mL) and it was combined with another batch of (5-bromo-2-methylphenyl)methanol and concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (2×) resulting in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (87.8 g), which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.48 (d, J=2.0 Hz, 1H), 7.28 (dd, J=8.1, 2.2 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.44 (s, 2H), 2.13 (s, 3H).

Step B: 5-Bromo-2-methylbenzyl pivalate. Pivaloyl chloride (119 mL, 966 mmol) was added drop-wise to a solution of (5-bromo-2-methylphenyl)methanol (87.8 g, 437 mmol), triethylamine (243 mL, 1.75 mol), and dichloromethane (800 mL) which had been cooled to 0° C. The resulting mixture was allowed to warm to room-temperature and stirred for 4 hours before pouring into water (600 mL). The aqueous layer was extracted with dichloromethane (2×). These extractions resulted in several organic fractions that were combined, washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether, isocratic) to afford the title compound (160 g, 96%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (d, J=2.2 Hz, 1H), 7.39 (dd, J=8.1, 2.2 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 5.03 (s, 2H), 2.21 (s, 3H), 1.13 (s, 9H).

Step C: 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl pivalate. 5-Bromo-2-methylbenzyl pivalate (40.0 g, 140 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (53.5 g, 211 mmol), KOAc (55.1 g, 561 mmol), and 1,4-dioxane (600 mL) were mixed and sparged with Na for 5 minutes and Pd(dppf)Cl₂ (8.2 g, 11 mmol) was added. The mixture was sparged again with Na for another 5 minutes and then heated at 90° C. for 4 hours before cooling to room-temperature, pouring it into H₂O (200 mL), and extracting with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. This material was combined with another batch of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl pivalate and purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1, isocratic) to give the product (120 g), which was further purified by preparative HPLC (stationary phase: SANPONT C18, 250 mm×50 mm×5 μm column, eluent: 50% to 95% (v/v) CH₃CN and H₂O with 0.1% TFA) to afford the titiled compound (77.1 g) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.60 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 5.09 (s, 2H), 2.31 (s, 3H), 1.28 (s, 12H), 1.14 (s, 9H).

Step D: 8-Methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine. 7-Bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (36.5 g, 130 mmol), potassium trifluoro(vinyl)borate (34.9 g, 261 mmol), K₃PO₄ (83.0 g, 391 mmol), 1,4-dioxane (350 mL), and H₂O (70 mL) were mixed and sparged with Ar for 5 minutes and then Pd(dppf)Cl₂ (4.8 g, 6.6 mmol) was added. This mixture was sparged with Ar for another 5 minutes and heated at 110° C. for 16 hours. The reaction was cooled to room-temperature, combined with another batch of 8-methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine and filtered through a pad of diatomaceous earth. The filtrate was poured into H₂O (160 mL), and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by FCC (eluent: petroleum ether/ethyl acetate, 10:1 to 3:1, gradient elution) to afford the title compound (48.4 g).

Step E: 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde. K₂OsO₄.2H₂O (1.6 g, 4.3 mmol) was added to a solution of 8-methyl-3-(trifluoromethyl)-7-vinyl-[1,2,4]triazolo[4,3-a]pyridine (24.0 g, 105 mmol), 1,4-dioxane (700 mL), and distilled H₂O (700 mL). NaIO₄ (72.3 g, 338 mmol) was then added and the reaction mixture allowed to stir at room-temperature for 2 hours. The suspension was filtered through a pad of diatomaceous earth, the filtrate combined with another batch of 8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridine-7-carbaldehyde, and concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether:/ethyl acetate, 10:1 to 3:1, gradient elution) to afford the title compound (45.2 g). MS (ESI): mass calcd. for C₉H₆F₃N₃O 229.1 m/z found 229.8 [M+H]⁺.

Step F: 5-(Hydroxy(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate. 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (25.6 g, 112 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl pivalate (44.54 g, 134.1 mmol), P(1-nap)₃ (18.4 g, 44.6 mmol), K₂CO₃ (77.2 g, 559 mmol), and THF (600 mL) were mixed and sparged with Ar for 5 minutes followed by addition of PdCl₂ (3.96 g, 22.3 mmol). The mixture was sparged with Na for another 5 minutes and then heated at 75° C. for 1 hour before cooling to room-temperature. The suspension was combined with two additional batches of 5-(hydroxy(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)methyl)-2-methylbenzyl pivalate, filtered, and the filter cake washed with methanol (2×). The filtrate was concentrated to dryness under reduced pressure and the residue purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 2:3, gradient elution) to afford the title compound (61 g). ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=7.1 Hz, 1H), 7.35-7.26 (m, 2H), 7.21-7.16 (m, 2H), 6.28 (d, J=4.2 Hz, 1H), 6.07 (d, J=4.2 Hz, 1H), 5.04 (s, 2H), 2.23 (s, 3H), 1.05 (s, 9H).

Step G: 5-(Chloro(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate. Thionyl chloride (117 mL, 1.61 mol) was added to a solution of 5-(hydroxy(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate (61.0 g, 140 mmol) and dichloromethane (1 L). The resulting mixture was stirred at room-temperature for 15 hours before concentrating to dryness under reduced pressure to afford the title compound (74 g), which was used in the next step without further purification.

Step H: Methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 5-(Chloro(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-2-methylbenzyl pivalate (69.0 g, 129 mmol), ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (74.3 g, 426 mmol), dichloromethane (1 L), and InBr₃ (10.54 g, 29.73 mmol) were mixed, sparged with Ar for 5 minutes and then stirred at room temperature under Ar for 18 hours. The reaction mixture was poured into aqueous saturated NaHCO₃ solution (250 mL) and extracted with dichloromethane (2×). These extractions resulted in several organic fractions that were dried over anhydrous MgSO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 100:1 to 3:1, gradient elution) to provide the title compound (31 g, 46%). MS (ESI): mass calcd. For C₂₇H₃₂F₃N₃O₄ 519.2 m/z found 520.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.3 Hz, 1H), 7.20 (d, J=7.3 Hz, 2H), 7.15 (d, J=7.8 Hz, 2H), 5.02 (s, 2H), 4.79 (s, 1H), 3.51 (s, 3H), 2.66 (s, 3H), 2.23 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H), 1.06 (s, 9H).

Step I: Methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Sodium methoxide (37.0 mL, 25 wt % in MeOH, 162 mmol) was added drop-wise to a solution of methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)propanoate (26 g, 50 mmol) and MeOH (250 mL). The resulting mixture was stirred at room-temperature for 2 hours, combined with another batch of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, poured into aqueous saturated NH₄Cl solution (200 mL), and extracted with DCM (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 100:1 to 1:1, gradient elution) to give the title compound (21 g) which was used in the next step without further purification.

Step J: (*R)-Methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate isomers were separated by chiral SFC (stationary phase: REGIS (s,s) WHELK-O1 250 mm×50 mm, 5 μm; eluent: 35% to 35% (v/v) supercritical CO₂ in IPA and H₂O with 0.1% NH₃). The second eluting isomer (8.5 g, 39%) was designated (*R). MS (ESI): mass calcd. For C₂₂H₂₄F₃N₃O₃ 435.2 m/z found 436.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.1 Hz, 1H), 7.30-7.25 (m, 2H), 7.13-7.09 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.04 (t, J=5.3 Hz, 1H), 4.76 (s, 1H), 4.43 (d, J=5.4 Hz, 2H), 3.51 (s, 3H), 2.68 (s, 3H), 2.17 (s, 3H), 1.32 (s, 3H), 1.28 (s, 3H).

Intermediate 142: Methyl (*R)-3-(3-((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiropyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The title compound (230 mg, 91%) was prepared using analogous conditions as described in Example 11 where methyl (*R) 3-(3-(hydroxy methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 141) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 7′-chloro-8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 132) instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₄H₃₇ClF₃N₅O₆S, 735.2; m/z found, 736.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=7.4 Hz, 1H), 8.00 (d, J=0.9 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.10 (d, J=1.4 Hz, 2H), 5.30 (s, 1H), 4.79 (s, 1H), 4.53-4.40 (m, 2H), 4.07-3.96 (m, 2H), 3.65-3.50 (m, 5H), 3.40 (d, J=15.4 Hz, 1H), 2.78 (s, 3H), 2.42 (s, 3H), 2.23 (s, 3H), 1.70 (ddd, J=19.5, 14.0, 2.6 Hz, 2H), 1.51 (ddd, J=13.5, 11.4, 4.9 Hz, 2H), 1.42 (s, 3H), 1.36 (s, 3H).

Intermediate 143: Methyl (*R)-3-(3-((7′-chloro-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The title compound (726 mg, 93%) was prepared using analogous conditions as described in Example 11 where methyl (*R) 3-(3-(hydroxy methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 141) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 7′-chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₂H₃₃ClF₃N₅O₅S, 691.2; m/z found, 692.2 [M+H]⁺.

Intermediate 144: 8′-Methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide

The title compound (667 mg, 61%) was prepared using analogous conditions as described in Intermediate 140 where 2-(pyrrolidin-1-yl)ethanol was used instead of 2-(piperidin-1-yl)ethanol in step C. MS (ESI): mass calcd. for C₁₈H₂₇N₃O₅S 397.5 m/z found 398.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (m, 1H), 7.84 (m, 1H), 4.43 (t, J=5.7 Hz, 2H), 3.87-3.74 (m, 2H), 3.62 (d, J=11.0 Hz, 2H), 3.44 (d, J=4.6 Hz, 2H), 2.92 (t, J=5.7 Hz, 2H), 2.68-2.63 (m, 4H), 2.14 (s, 3H), 1.75-1.67 (m, 4H), 1.60 (s, 4H).

Intermediate 145: Methyl (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate

The mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate isomers (Intermediate 48) were separated by chiral SFC (stationary phase: REGIS (s,s) WHELK-O1 250 mm×50 mm, 5 μm; eluent: 35% to 35% (v/v) supercritical CO₂ in IPA and H₂O with 0.1% NH₃). The first eluting isomer (8.5 g, 39%) was designated (*S). MS (ESI): mass calcd. For C₂₂H₂₄F₃N₃O₃ 435.2 m/z found 436.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.3 Hz, 1H), 7.31-7.25 (m, 2H), 7.13-7.09 (m, 1H), 7.06 (d, J=7.6 Hz, 1H), 5.03 (t, J=5.3 Hz, 1H), 4.76 (s, 1H), 4.43 (d, J=5.0 Hz, 2H), 3.51 (s, 3H), 2.68 (s, 3H), 2.17 (s, 3H), 1.32 (s, 3H), 1.28 (s, 2H), 1.30-1.25 (m, 1H).

Intermediate 146: 7′-(2-Morpholinoethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 6-Bromo-2-chloropyridine-3-sulfonyl chloride. HBF₄ (32.0 mL, 206 mmol) was added drop-wise to a solution of 6-bromo-2-chloropyridin-3-amine (30.0 g, 145 mmol) and acetonitrile (150 mL) which had been cooled to 0° C. The resulting mixture was stirred at 0° C. for 10 minutes. Then tert-butyl nitrite (26.0 mL, 219 mmol) was added drop-wise and the reaction mixture was allowed to stir at 0° C. for 1 hour to form a 6-bromo-2-chloropyridine-3-diazonium tetrafluoroborate solution. In a separate flask, copper(I) chloride (22.0 g, 222 mmol) and acetic acid (120 mL) were mixed and cooled to 0° C. SO₂ gas (>1.3 M) was bubbled through the mixture which was maintained at 0° C. for 1 hour. At this time the 6-bromo-2-chloropyridine-3-diazonium tetrafluoroborate solution, which had been cooled to 0° C., was added dropwise. The resulting mixture was stirred for 12 hours with gradual warming to room-temperature. The suspension was filtered through a pad of diatomaceous earth and the pad washed with ethyl acetate (1×). The resulting mixture was quenched with aqueous saturated NaHCO₃ solution (200 mL), stirred for 20 minutes, and then extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with water (2×) and brine (1×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 10:1, gradient elution) to afford the title compound (24 g), which was used in the next step without further purification.

Step B: 6-Bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide. A solution of 6-bromo-2-chloropyridine-3-sulfonyl chloride (48 g) and THF (100 mL) was added drop-wise to a mixture of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (20.0 g, 152 mmol), K₂CO₃ (65.0 g, 470 mmol), THF (100 mL), and H₂O (50 mL) which had been cooled to 0° C. This reaction mixture was stirred for 12 hours with gradual warming to room-temperature before concentrating to dryness under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 1:1, gradient elution) to afford the title compound (35 g), which was used in the next step without further purification.

Step C: 7′-Bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide. t-BuOK (5.5 g, 49 mmoL) was added in portions to a solution of 6-bromo-2-chloro-N-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)pyridine-3-sulfonamide (10 g) and DMSO (40 mL) which had been cooled to 0° C. The resulting mixture was heated at 100° C. for 2 hours before concentrating to dryness under reduced pressure. The residue was diluted with H₂O (50 mL) and the pH of the solution was adjusted to pH=6 with 1 N HCl (20 mL). The suspension was isolated via filtration and the filter cake washed with petroleum ether (20 mL) before drying under reduced pressure to provide the product (7.0 g), which was combined with another batch of the title compound (14 g), to provide 21 g of the title compound. The product (21 g) was then triturated with ethyl acetate (30 mL) and the suspension isolated via filtration. The filter cake was washed with petroleum ether/ethyl acetate (10:1, 50 mL) before drying under reduced pressure to afford the title compound (18.5 g). MS (ESI): mass calcd. for C₁₁H₁₃BrN₂O₄S 348.0, m/z found 349.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54-8.47 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 3.76-3.66 (m, 2H), 3.62-3.55 (m, 2H), 3.49 (d, J=6.4 Hz, 2H), 1.68-1.53 (m, 4H).

Step D: 7′-((2-Morpholinoethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. Sodium hydride in mineral oil (5.20 g, 60% purity, 130 mmol) was added in portions to a solution of 2-morpholinoethanol (14.0 g, 107 mmol) and toluene (150 mL) which had been cooled to 0° C. The resulting mixture was stirred for 0.5 hours with gradual warming to room-temperature and was then treated with 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (18 g, 52 mmol), S-tol-BINAP (1.4 g, 2.1 mmol), and Pd₂(dba)₃ (930 mg, 1.02 mmol). This reaction mixture was heated at 110° C. for 16 hours before quenching with acetic acid (8 mL). The suspension was filtered through a pad of diatomaceous earth and the pad washed with ethyl acetate (500 mL). The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 0:1, gradient elution) to afford the title compound (8.0 g, 38%). The mixture was combined with another batch of the title compound and triturated with petroleum ether/ethyl acetate, 10:1 (50 mL) and the suspension was isolated via filtration. The filter cake was washed with petroleum ether (50 mL) before drying under reduced pressure to afford the title compound (14.2 g). MS (ESI): mass calcd. for C₁₇H₂₅N₃O₆S 399.5 m/z found 400.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22-8.14 (m, 1H), 7.95 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 4.42-4.30 (m, 2H), 3.83-3.71 (m, 2H), 3.64-3.56 (m, 2H), 3.55-3.50 (m, 4H), 3.46-3.40 (m, 2H), 2.68-2.61 (m, 2H), 2.45-2.38 (m, 4H), 1.65-1.51 (m, 4H).

Intermediate 147: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde

Step A: 4-Iodo-5-methylpyridin-2(1H)-one. Concentrated HCl (12 M, 400 mL, 4.80 mol) was added to a mixture of 2-fluoro-4-iodo-5-methylpyridine (200 g, 844 mmol), 1,4-dioxane (400 mL), and H₂O (400 mL). The resulting mixture was heated at 100° C. for 2 hours, then cooled to room temperature and poured into H₂O (1200 mL). The resulting suspension was stirred for 16 hours and then isolated via filtration. The filter cake was washed with water (100 mL×3) and dried under reduced pressure to give the title compound (116 g). MS (ESI): mass calcd. for C₆H₆INO 234.95; m/z found, 235.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (br. s., 1H), 7.26 (s, 1H), 7.00 (s, 1H), 2.04 (s, 3H).

Step B: Methyl 5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate. 4-Iodo-5-methylpyridin-2(1H)-one (60.0 g, 255 mmol) and K₂CO₃ (70.57 g, 510.6 mmol) were added to a 2 L round-bottomed flask and the resulting mixture was treated with MeOH (1000 mL). The mixture was sparged with Argon for 5 minutes and then treated with Pd(OAc)₂ (6.88 g, 30.6 mmol) and dcpp.BF₄ (31.26 g, 51.06 mmol). The resulting mixture was heated at 80° C. for 48 hours under CO (50 psi) atmosphere, then the reaction mixture was cooled to room temperature. The mixture was combined with another batch of methyl 5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate and then filtered and washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was poured into H₂O (1500 mL) and the pH of the mixture was adjusted to pH=5 with concentrated HCl. The mixture was then filtered and extracted with ethyl acetate (1 L×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure to give the title compound (34 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₈H₉NO₃ 167.06; m/z found, 167.8 [M+H]⁺.

Step C: Methyl 2-chloro-5-methylisonicotinate. Methyl 5-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (68 g) was added to a 1 L round-bottomed flask containing POCl₃ (600 g, 3.91 mol). The resulting mixture was stirred at 110° C. for 16 hours, then was cooled to room temperature and concentrated under reduced pressure. The mixture was poured into H₂O (600 mL) and extracted with ethyl acetate (600 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 10:1) to give the title compound (38 g, 48% yield). MS (ESI): mass calcd. for C₈H₈ClNO₂ 185.02; m/z found, 186.0 [M+H]⁺.

Step D: (2-chloro-5-methylpyridin-4-yl)methanol. NaBH₄ (11.4 g, 301 mmol) was added to a solution of methyl 2-chloro-5-methylisonicotinate (28.0 g, 151 mmol), NaOMe (407 mg, 7.53 mmol), and MeOH (400 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then was quenched with H₂O (400 mL) and extracted with ethyl acetate (400 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (21 g), which was used in next step without further purification. MS (ESI): mass calcd. for C₇H₈ClNO 157.03; m/z found, 157.8 [M+H]⁺.

Step E: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-chloro-5-methylpyridine. TBSCl (26.1 g, 173 mmol) was added to a solution of (2-chloro-5-methylpyridin-4-yl)methanol (21.0 g, 133 mmol), 1H-imidazole (27.2 g, 400 mmol), and dichloromethane (500 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The material was purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 10:1) to give the title compound (35 g, 97% yield). MS (ESI): mass calcd. for C₁₃H₂₂ClNOSi 271.1; m/z found, 272.1 [M+H]⁺.

Step F: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-2-vinylpyridine. 4-(((tert-Butyldimethylsilyl)oxy)methyl)-2-chloro-5-methylpyridine (35.0 g, 129 mmol) was added to a mixture of potassium trifluoro(vinyl)borate (34.4 g, 257 mmol), K₃PO₄ (82.0 g, 386 mmol), 1,4-dioxane (400 mL), and H₂O (100 mL). The resulting mixture was sparged with Na for 5 minutes and then treated with Pd(dppf)Cl₂ (4.71 g, 6.44 mmol). The resulting mixture was sparged with Na for another 5 minutes and then stirred and heated at 90° C. for 13 hours under an atmosphere of Na. After this period of time, the reaction was cooled to room temperature, filtered through a pad diatomaceous earth, such as of Celite®, and the pad was washed with ethyl acetate (200 mL). The filtrate was poured into water (500 mL) and the resulting mixture was extracted with ethyl acetate (500 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified in two batches by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 10:1) to give the title compound (batch 1: 22 g, 65% yield; batch 2: 10 g, 27% yield). MS (ESI): mass calcd. for C₁₃H₂₂ClNOSi 263.17; m/z found, 264.3 [M+H]⁺.

Step G: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde.

K₂OsO₄.H₂O (559 mg, 1.52 mmol) was added to a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-2-vinylpyridine (10.0 g, 38.0 mmol), 1,4-dioxane (200 mL), and H₂O (200 mL). The resulting mixture was treated with NaIO₄ (26.0 g, 122 mmol) and stirred at room temperature for 5 hours. The mixture was then filtered through a pad diatomaceous earth, such as of Celite® and the pad washed with ethyl acetate (100 mL). The filtrate was quenched with H₂O (200 mL) and extracted with ethyl acetate (200 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was combined with another batch of the same compound and purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 10:1) to give the title compound (5.9 g). MS (ESI): mass calcd. for C₁₄H₂₃NO₂Si 265.15; m/z found, 266.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.55 (s, 1H), 7.95 (s, 1H), 4.79 (s, 2H), 2.29 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H).

Intermediate 148: 3-(Difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine

Step A: 2-Hydrazinyl-4-iodo-3-methylpyridine. To 2-fluoro-4-iodo-3-methylpyridine (23.4 g, 98.7 mmol) was added hydrazine hydrate (47 mL, 630 mmol). The resulting mixture was heated at 60° C. for 24 hours before being allowed to cool to room temperature. 3N NaOH solution (60 mL) and water (60 mL) were added to the reaction mixture and stirred for 30 minutes. The resulting precipitate was isolated by filtration and the filter cake was washed with water and dried under reduced pressure to afford the title compound (20.4 g, 83% yield). MS (ESI): mass calcd. for C₆H₈IN₃ 249.0; m/z found, 250.0 [M+H]⁺.

Step B: 3-(Difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. 2,2,2-Trifluoroacetic anhydride (18.9 mL, 162 mmol) was added dropwise to 2-hydrazinyl-4-iodo-3-methylpyridine (26.9 g, 108 mmol). The resulting mixture was stirred at 90° C. for 20 hours before being allowed to cool to room temperature. The pH of the reaction mixture was adjusted to pH=8 with aqueous saturated Na₂CO₃. The resulting biphasic mixture was separated and the organic layer was washed with water and brine. The organic layer was then dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was triturated with hexanes and ethyl acetate, and the solid was filtered to provide the title compound (29.6 g, 88.7% yield). MS (ESI): mass calcd. for C₈H₆F₂IN₃ 308.96; m/z found, 310.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.95 (m, 1H), 7.35-7.30 (m, 1H), 7.39-7.10 (m, 1H), 2.86-2.81 (m, 3H).

Intermediate 149: 3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-carbaldehyde

Step A: N,6-Dimethylpyridazin-3-amine. Into a 5000-mL pressure tank reactor, was placed 3-chloro-6-methylpyridazine (200 g, 1.56 mol) and CH₃NH₂/MeOH (3000 mL, 30% wt). The resulting solution was heated overnight at 110° C. After this time, the reaction mixture was cooled and concentrated under reduced pressure. The residue was washed with 1000 mL of petroleum ether and dried in an oven under reduced pressure to provide the title compound (210 g), which was used in the next step without further purification.

Step B: 4-Bromo-N,6-dimethylpyridazin-3-amine. Into a 5000-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed N,6-dimethylpyridazin-3-amine (210 g, 1.71 mol), acetic acid (2100 mL), sodium acetate (140 g, 1.71 mol), and bromine (809 g, 5.06 mol). The resulting solution was heated overnight at 65° C. After this time, the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The reaction was then quenched by the addition of 2000 mL of saturated aqueous NaHCO₃ solution. The pH of the solution was adjusted to pH=9 using additional aqueous saturated sodium bicarbonate solution and then the solution was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (dichloromethane/methanol, 40:1) to give the title compound (64 g, 19% yield over two steps).

Step C: 4-(3,3-Diethoxyprop-1-yn-1-yl)-N,6-dimethylpyridazin-3-amine. Into a 250-mL 3-necked round-bottom flask, was placed 4-bromo-N,6-dimethylpyridazin-3-amine (10 g, 49.49 mmol), N,N-dimethylformamide (100 mL), TEA (25.12 g, 248.25 mmol), and 3,3-diethoxyprop-1-yne (7.64 g, 59.61 mmol). The solution was sparged with N₂ for 5 min. Then, dichloropalladium bis(triphenylphosphane) (1.74 g, 2.48 mmol) and copper iodide (940 mg, 4.94 mmol) were added. The resulting solution was heated at 50° C. for 2 hours. After this time, the reaction mixture was allowed to cool to room temperature. The reaction was then quenched with 400 mL of saturated aqueous NaHCO₃ solution and extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (ethyl acetate/petroleum ether, 1:2) to give the title compound (9.9 g, 80% yield).

Step D: 6-(Diethoxymethyl)-3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(3,3-diethoxyprop-1-yn-1-yl)-N,6-dimethylpyridazin-3-amine (10 g, 40.11 mmol) and NMP (100 mL) then the solution was cooled to 0° C. KO^(t)Bu (1.8 g, 16.04 mmol) was then added and the reaction mixture was allowed to warm to room temperature. The resulting solution was stirred for 1 hour. The reaction was then quenched by the addition of 200 mL of water/ice and extracted with ethyl acetate (3×100 mL). These extractions resulted in several organic solvent fractions which were combined, washed with saturated aqueous NaCl (2×100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by preparative basic HPLC (CombiFlash-1, C18 silica gel, mobile phase: ACN/H₂O (5 mmol/L NH₄HCO₃)=30/70 increasing to ACN/H₂O (5 mmol/L NH₄HCO₃)=40/70), to give the title compound (6.0 g, 60% yield).

Step E: 3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-carbaldehyde. Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-(diethoxymethyl)-3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine (10 g, 40.11 mmol) and 1,4-dioxane (100 mL) which had been cooled to 0° C. 6N Hydrogen chloride (100 mL) was the added and the reaction mixture was allowed to warm to room temperature. The resulting solution was stirred for 4 hours. The resulting solution was extracted with ethyl acetate (2×200 mL) and the pH of the aqueous layer was adjusted to pH=9 using saturated aqueous NaHCO₃ solution. The resulting aqueous solution was extracted with ethyl acetate (3×200 mL). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (6.0 g, 85% yield). MS (ESI): mass calcd. for C₉H₉N₃O 175.07; m/z found, 176.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 4.15 (s, 3H), 2.73 (s, 3H).

Intermediate 150: tert-Butyl 2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide

Step A: tert-Butyl 4-((2-chloropyridine-3-sulfonamido)methyl)-4-hydroxypiperidine-1-carboxylate. 2-Chloropyridine-3-sulfonyl chloride (6.0 g, 28 mmol) was added dropwise to mixture of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (6.52 g, 28.3 mmol), K₂CO₃ (9.78 g, 70.8 mmol), THF (100 mL), and H₂O (20 mL) which had been cooled to a 0° C. The resulting mixture was stirred at 0° C. for 4 hours, then was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with petroleum ether/ethyl acetate (10:1, 50 mL) and the solid was isolated via filtration. The filter cake was washed with petroleum ether/ethyl acetate (10:1, 5 mL×2) and dried under reduced pressure to give the title compound (6.8 g, 52% yield). MS (ESI): mass calcd. for C₁₆H₂₄ClN₃O₅S 405.11; m/z found, 305.9 [M-Boc+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (dd, J=4.8, 1.8 Hz, 1H), 8.33 (dd, J=7.8, 2.0 Hz, 1H), 8.01 (t, J=6.3 Hz, 1H), 7.63 (dd, J=7.8, 4.8 Hz, 1H), 3.61 (d, J=11.0 Hz, 2H), 2.99 (br s, 2H), 2.88 (d, J=6.3 Hz, 2H), 1.41 (br s, 1H), 1.38 (s, 9H), 1.36-1.29 (m, 3H).

Step B: tert-Butyl 2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. t-BuOK (4.7 g, 42 mmol) was added to a solution of tert-butyl 4-((2-chloropyridine-3-sulfonamido)methyl)-4-hydroxypiperidine-1-carboxylate (6.8 g, 17 mmol) and DMSO (70 mL) which had been cooled to 0° C. The resulting mixture was stirred at 90° C. for 16 hours, then was allowed to cool to room temperature and concentrated to dryness under reduced pressure at 110° C. The residue was diluted with water (50 mL) and the mixture extracted with ethyl acetate (60 mL×4). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 2:3, gradient elution) to give the title compound (4.8 g, 74% yield). MS (ESI): mass calcd. for C₁₆H₂₃N₃O₅S 369.14; m/z found, 370.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.53-8.46 (m, 1H), 8.45-8.38 (m, 1H), 8.19-8.12 (m, 1H), 7.44-7.36 (m, 1H), 3.70-3.55 (m, 2H), 3.54-3.43 (m, 2H), 3.33-3.14 (m, 2H), 1.70-1.57 (m, 2H), 1.56-1.45 (m, 2H), 1.38 (s, 9H).

Intermediate 151: tert-Butyl 2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide

The title compound (6.3 g, 55% yield) was prepared using analogous conditions as described in Intermediate 150 where tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate was used instead of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate. MS (ESI): mass calcd. for C₁₄H₂₀ClN₃O₅S 341.10; m/z found, 286.1 [M-t-Bu+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58-8.51 (m, 1H), 8.36-8.26 (m, 1H), 8.24-8.16 (m, 1H), 7.53-7.44 (m, 1H), 3.93-3.83 (m, 2H), 3.82-3.75 (m, 2H), 3.71-3.59 (m, 2H), 1.37 (s, 9H).

Intermediate 152: tert-Butyl 8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide

The title compound (8.3 g, 67% yield) was prepared using analogous conditions as described in Intermediate 150 where 2-chloro-5-methylpyridine-3-sulfonyl chloride was used instead of 2-chloropyridine-3-sulfonyl chloride. MS (ESI): mass calcd. for C₁₇H₂₅N₃O₅S 383.15; m/z found, 384.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.32 (m, 1H), 8.31-8.29 (m, 1H), 7.98-7.94 (m, 1H), 3.73-3.54 (m, 2H), 3.51-3.41 (m, 2H), 3.32-3.16 (m, 2H), 2.34 (s, 3H), 1.66-1.57 (m, 2H), 1.55-1.44 (m, 2H), 1.39 (s, 9H).

Intermediate 153: tert-Butyl 8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide

The title compound (3.8 g, 62% yield) was prepared using analogous conditions as described in Intermediate 150 where 2-chloro-5-methylpyridine-3-sulfonyl chloride was used instead of 2-chloropyridine-3-sulfonyl chloride and tert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate was used instead of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate. MS (ESI): mass calcd. for C₁₅H₂₀N₃O₅S 355.12; m/z found, 300.1 [M-t-Bu+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 3.84 (d, J=9.0 Hz, 2H), 3.76 (s, 2H), 3.65 (d, J=8.8 Hz, 2H), 2.35 (s, 3H), 1.37 (s, 9H).

Intermediate 154: (*S)-2′,3′,4,5-Tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 3-Hydroxytetrahydrofuran-3-carbonitrile. BF₃.Et₂O (105 g, 738 mmol) was added to a stirring solution of dihydrofuran-3(2H)-one (60.5 g, 703 mmol) and TMSCN (73.2 g, 738 mmol) in THF (1.2 L) while maintaining the temperature below 20° C. After 16 hours, saturated aqueous sodium bicarbonate solution was added until the pH was 7. The mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. This resulted in several organic fractions which were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound (45 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 4.09-3.91 (m, 4H), 2.52-2.42 (m, 1H), 2.37-2.28 (m, 1H).

Step B: 3-(Aminomethyl)tetrahydrofuran-3-ol. A solution of 3-hydroxytetrahydrofuran-3-carbonitrile (20.5 g, 181 mmol) in THF (80 mL) was added dropwise to a stirring solution of LAH (7.57 g, 199 mmol) in THF (200 mL) at 0° C. After 3 hours, water (7.6 mL), 15% aqueous sodium hydroxide solution (7.6 mL), and then water (7.6 mL) were added dropwise, sequentially. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound as a colorless liquid (15 g). This material was used in the next step without further purification.

Step C: 2-Chloro-N-((3-hydroxytetrahydrofuran-3-yl)methyl)pyridine-3-sulfonamide. 2-Chloropyridine-3-sulfonyl chloride (25.9 g, 122 mmol) was added to a stirring solution of 3-(aminomethyl)tetrahydrofuran-3-ol (15 g, 128 mmol) and potassium carbonate (42.1 g, 305 mmol) in a mixture of THF (300 mL) and water (75 mL) at 0° C. The mixture was allowed to warm to room temperature. After 16 hours, water (150 mL) was added and the mixture was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. This resulted in numerous organic fractions which were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound (16.7 g, 46%). MS (ESI): mass calcd. for C₁₀H₁₃ClN₂O₄S, 292.0; m/z found, 293.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (dd, J=4.8, 1.9 Hz, 1H), 8.40 (dd, J=7.8, 1.9 Hz, 1H), 7.45 (dd, J=7.8, 4.8 Hz, 1H), 5.95 (t, J=6.2 Hz, 1H), 4.05-3.94 (m, 1H), 3.91-3.82 (m, 1H), 3.69 (d, J=9.7 Hz, 1H), 3.62 (d, J=9.7 Hz, 1H), 3.18-3.07 (m, 2H), 2.88 (s, 1H), 1.99-1.92 (m, 2H).

Step D: (*S)-2′,3′,4,5-Tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. A mixture of 2-chloro-N-((3-hydroxytetrahydrofuran-3-yl)methyl)pyridine-3-sulfonamide (3 g, 10 mmol) and potassium tert-butoxide (3.45 g, 30.7 mmol) in DMF (60 mL) was warmed to 80° C. After 1 hour, the mixture was cooled to room temperature and then a solution of 4 M HCl in methanol was added until the pH was 7. The mixture was concentrated under reduced pressure to afford a mixture of 2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide enantiomers (4 g). This was combined with an additional batch of 2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide enantiomers (2.9 g). The isomers were separated by chiral SFC (stationary phase: Chiralcel OJ 10 μm 250×50 mm, mobile phase: 60% CO₂ and 40% methanol with 0.1% NH₃) to afford two enantiomers. The first eluting enantiomer (2.8 g) was designated (*S). MS (ESI): mass calcd. for C₁₀H₁₂N₂O₄S, 256.1; m/z found, 256.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (dd, J=4.8, 2.0 Hz, 1H), 8.32 (s, 1H), 8.19 (dd, J=7.6, 2.0 Hz, 1H), 7.43 (dd, J=7.6, 4.8 Hz, 1H), 4.02-3.94 (m, 1H), 3.89-3.81 (m, 1H), 3.77-3.58 (m, 4H), 2.02-1.90 (m, 1H), 1.86-1.78 (m, 1H).

Intermediate 155: (*R)-2′,3′,4,5-Tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The second eluting isomer (2.8 g) from the chiral separation described in Intermediate 154 was designated (*R). MS (ESI): mass calcd. for C₁₀H₁₂N₂O₄S, 256.1; m/z found, 256.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (dd, J=4.8, 1.9 Hz, 1H), 8.30 (s, 1H), 8.17 (dd, J=7.7, 1.9 Hz, 1H), 7.41 (dd, J=7.6, 4.9 Hz, 1H), 4.00-3.92 (m, 1H), 3.87-3.78 (m, 1H), 3.74-3.56 (m, 4H), 1.99-1.90 (m, 1H), 1.85-1.76 (m, 1H).

Intermediate 156: (*S)-8′-Methyl-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (2.6 g) was prepared using analogous conditions as described in Intermediate 154 using 2-chloro-5-methylpyridine-3-sulfonyl chloride instead of 2-chloropyridine-3-sulfonyl chloride in Step C. MS (ESI): mass calcd. for C₁₁H₁₄N₂O₄S, 270.1; m/z found, 270.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 4.02-3.92 (m, 1H), 3.87-3.80 (m, 1H), 3.74-3.56 (m, 4H), 2.35 (s, 3H), 2.00-1.88 (m, 1H), 1.85-1.76 (m, 1H).

Intermediate 157: (*R)-8′-Methyl-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The second eluting isomer (2.8 g) from the chiral separation described in Intermediate 156 was designated (*R). MS (ESI): mass calcd. for C₁₁H₁₄N₂O₄S, 270.1; m/z found, 270.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 8.00 (d, J=2.4 Hz, 1H), 4.02-3.92 (m, 1H), 3.87-3.80 (m, 1H), 3.73-3.53 (m, 4H), 2.35 (s, 3H), 1.99-1.88 (m, 1H), 1.87-1.76 (m, 1H).

Intermediate 160: Methyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Thionyl chloride (1.5 mL, 21 mmol) was added to a stirring solution of methyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 141, 400 mg, 0.919 mmol) in dichloromethane (5 mL). After 16 hours, the mixture was concentrated under reduced pressure to afford the title compound (420 mg). This material was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.28-7.22 (m, 2H), 7.18-7.14 (m, 1H), 4.76 (s, 1H), 4.72 (s, 2H), 3.51 (s, 3H), 2.68 (s, 3H), 2.31 (s, 3H), 1.31 (s, 3H), 1.27 (s, 3H).

Intermediate 161: Methyl (*R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The title compound (420 mg) was prepared using analogous conditions as described in Intermediate 160 using methyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 145) instead of methyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=7.3 Hz, 1H), 7.33 (s, 1H), 7.29-7.22 (m, 2H), 7.19-7.15 (m, 1H), 4.76 (s, 1H), 4.73 (s, 2H), 3.50 (s, 3H), 2.69 (s, 3H), 2.32 (s, 3H), 1.31 (s, 3H), 1.27 (s, 3H).

Intermediate 162: 3-Cyclopropyl-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine

Cyclopropanecarbaldehyde (6.9 mL, 92 mmol) was added to a suspension of 2-hydrazinyl-4-iodo-3-methylpyridine (Intermediate 52, 20 g, 80 mmol) in DCM (80 mL) at room temperature. The mixture was stirred for 30 minutes at room temperature, then was cooled in an ice bath. Phenyl-13-iodanediyl diacetate (31 g, 96 mmol) was added portion-wise over 2 minutes, then the reaction was removed from the ice bath and allowed to warm to room temperature overnight. The mixture became a solution while stirring overnight. The reaction was diluted with water and DCM. The resulting biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. A mixture of DCM and hexanes was used to precipitate the title compound (18.4 g, 77% yield). MS (ESI): mass calcd. for C₁₀H₁₀IN₃, 299.0; m/z found, 300.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21-8.17 (m, 1H), 7.27 (d, J=7.1 Hz, 1H), 2.58 (s, 3H), 2.40-2.30 (m, 1H), 1.16-0.94 (m, 4H).

Intermediate 163: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylbenzaldehyde

Step A: tert-Butyldimethyl((2-methyl-5-vinylbenzyl)oxy)silane. A mixture of ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 75 g, 238 mmol), potassium trifluoro(vinyl)borate (65 g, 485 mmol), and potassium phosphate (150 g, 707 mmol) in water (100 mL) and 1,4-dioxane (500 mL) was sparged with argon for 5 minutes. Pd(dppf)Cl₂ (9 g, 12 mmol) was added to the reaction and the resulting mixture was sparged with argon for 5 minutes. The reaction was then heated to 110° C. overnight. After this period of the time, the reaction was allowed to cool to room temperature and the suspension was filtered. The filtrate was diluted with water and extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (5-10% EtOAc/hexanes) to afford the title compound (50 g, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.13-7.03 (m, 1H), 7.01-6.91 (m, 1H), 6.59 (m, 1H), 5.60 (m, 1H), 5.07 (m, 1H), 4.64-4.51 (m, 2H), 2.14 (s, 3H), 0.90-0.80 (m, 9H), 0.08-0.03 (m, 6H)

Step B: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylbenzaldehyde. Potassium dioxidodioxoosmium dihydrate (9 g, 24 mmol) was added to a solution of tert-butyldimethyl((2-methyl-5-vinylbenzyl)oxy)silane (Intermediate 163, Step A, 110 g, 419 mmol) in water (500 mL) and 1,4-dioxane (500 mL). Sodium periodate (270 g, 1262 mmol) was added and the resultant mixture stirred at room temperature for 3 hours. The reaction was diluted with water and extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (5-10% EtOAc/hexanes) and then purified by preparative basic HPLC (SANPONT C18, acetonitrile-water, 10 mM NH₄HCO₃) to afford the title compound (82.7 g, 74% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.85 (s, 1H), 7.81 (s, 1H), 7.61-7.51 (m, 1H), 7.18-7.13 (m, 1H), 4.62 (s, 2H), 2.22 (s, 3H), 0.83 (s, 9H), 0.03-0.10 (m, 6H).

Intermediate 164: 7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde

Et₃N (2.8 g, 28 mmol) and triethylsilane (4.9 g, 42 mmol) were added 5-bromo-7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazole (3.8 g, 14 mmol), 1,3-bis(diphenylphosphino)propane (620 mg, 1.50 mmol), and DMF (60 mL). The resultant mixture was sparged with N₂ for 5 minutes and then treated with Pd(OAc)₂ (307 mg, 1.37 mmol) and Pd(dppf)₂Cl₂ (440 mg, 0.601 mmol). The mixture was stirred while heating at 80° C. under CO atmosphere (50 Psi) for 16 hours before cooling to room-temperature, pouring it into water (60 mL) and extracting with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title product, which was purified by FCC (eluent: petroleum ether:ethyl acetate=10:1 to 2:1) to afford the title compound (1.38 g, 44%) as a yellow solid. MS (ESI) mass calcd. for C₉H₇F₂N₃O₂ 227.05 m/z found 228.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.16-10.03 (m, 1H), 8.63 (s, 1H), 7.80-7.33 (m, 2H), 4.44 (s, 3H)

Intermediate 165: 8-fluoro-2,2′,3,3′,5′,6′-hexahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran] 1,1-dioxide

8-Fluoro-2,2′,3,3′,5′,6′-hexahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran] 1,1-dioxide (1.4 g, 50% yield) was prepared using analogous conditions as described in Intermediate 36 where 2,5-difluorobenzenesulfonyl chloride was used instead of 2-chloropyridine-3-sulfonyl chloride in Step A. MS (ESI): mass calcd. for C₁₂H₁₄FNO₄S, 287.06; m/z found, 288.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) □ 7.54-7.45 (m, 1H), 7.45-7.36 (m, 1H), 7.36-7.22 (m, 1H), 4.67-4.49 (m, 1H), 3.90-3.78 (m, 2H), 3.77-3.65 (m, 2H), 3.59-3.45 (s, 2H), 1.77-1.62 (m, 4H).

Intermediate 166: 8′-fluoro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

8′-Fluoro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (350 mg, 24.4% yield) was prepared using analogous conditions as described in Intermediate 36 where 2-chloro-5-fluoropyridine-3-sulfonyl chloride was used instead of 2-chloropyridine-3-sulfonyl chloride in Step A. MS (ESI): mass calcd. for C₁₁H₁₃FN₂O₄S, 288.06; m/z found, 289.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) □ 8.53 (t, J=3.1 Hz, 1H), 8.34-8.15 (m, 1H), 4.59 (s, 2H), 3.79-3.64 (m, 3H), 3.08-2.95 (m, 2H), 1.74-1.59 (m, 2H), 1.59-1.39 (m, 2H).

Intermediate 167: Ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

The mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate isomers (Example 28, Step C) were separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting isomer (2.42 g) was designated (*S): MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 403.4; m/z found, 404.2 [M+H]⁺. The second eluting isomer was designated as (*R), however this Intermediate was not used further.

Intermediate 168: Methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate

Step A: 1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde. Osmium tetroxide (0.40 mL, 1.56 mmol) was added to a stirring mixture of ethyl (E)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (Intermediate 17, 1.0 g, 3.86 mmol) in dioxane (25 mL) and water (25 mL) at room temperature. Then sodium periodate (2.61 g, 12.2 mmol) was added immediately. After one and half hours, ethyl acetate and water were added until all solids dissolved. The layers were separated, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (500 mg, 68%) as a white foam. MS (ESI): mass calcd. for C₁₀H₁₁N₃O, 189.1; m/z found, 190.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 10.50 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.45 (dt, J=8.6, 0.7 Hz, 1H), 4.72 (q, J=7.4 Hz, 2H), 3.14 (s, 3H), 1.66 (t, J=7.4 Hz, 3H).

Step B: (6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. n-Butyllithium (2.0 M, 3.1 ml, 6.2 mmol) was added dropwise to a solution of 6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpyridine (Intermediate 120, 1.25 g, 3.96 mmol) in THF (14 ml) at −78° C. under nitrogen. The reaction was stirred at −78° C. for 2 minutes to prepare the lithiate reaction mixture. A solution 1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (750 mg, 3.96 mmol) in THF (10 ml) was added to the lithiate reaction mixture dropwise. The resulting reaction mixture was stirred at −78° C. for 5 minutes. The reaction was then quenched with saturated aqueous NaHCO₃, and then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (800 mg, 47%). MS (ESI): mass calcd. for C₂₃H₃₄N₄O₂Si, 426.2; m/z found, 427.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.25 (dd, J=8.3, 1.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.04 (s, 1H), 5.64 (s, 1H), 4.79 (d, J=0.9 Hz, 2H), 4.53 (q, J=7.3 Hz, 2H), 2.80 (s, 3H), 2.28 (s, 3H), 1.47 (t, J=7.3 Hz, 3H), 0.81 (s, 9H), 0.00 (d, J=1.1 Hz, 6H).

Step C: Methyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Trichloroacetonitrile (0.49 ml, 4.88 mmol) and DBU (0.04 ml, 0.28 mmol) were added to a solution of (6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (800 mg, 1.88 mmol) in ACN (22 ml). The reaction was stirred at room temperature under nitrogen for 1 hour. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.76 ml, 3.75 mmol) was then added to the reaction, followed by trifluoromethanesulfonamide (263 mg, 0.94 mmol), and the reaction was stirred at room temperature under nitrogen for 3 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (eluent: 0-50% ethyl acetate/hexanes) to provide the title compound that was carried forward without further purification (600 mg, 63%). MS (ESI): mass calcd. for C₂₈H₄₂N₄O₃Si, 510.3; m/z found, 511.3 [M+H]⁺.

Step D: Methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 2.35 ml, 2.35 mmol) was added to a solution of methyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (600 mg, 1.18 mmol) and 3 drops of DMF in THF (25 ml). The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure. The product was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (350 mg, 75%). MS (ESI): mass calcd. for C₂₂H₂₈N₄O₃, 396.2; m/z found, 397.2 [M+H]⁺.

Intermediate 169: Methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: (4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. n-Butyllithium (2.0 M, 3.1 ml, 6.2 mmol) was added dropwise to a solution of 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (Intermediate 46, 4.0 g, 12.6 mmol) in THF (47 ml) at −78° C. under nitrogen. The reaction was stirred at −78° C. for 2 minutes to prepare the lithiate reaction mixture. A solution of 3-(trifluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine7-carbaldehyde (Intermediate 28, 2.6 g, 10.3 mmol) in THF (10 ml) was added to the lithiate reaction mixture dropwise. The resulting reaction mixture was stirred at −78° C. for 5 minutes. The reaction was then quenched with saturated aqueous NaHCO₃, and then extracted twice with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (eluent: 0-100% EtOAc/hexanes) to provide the title compound (3.0 g, 63%). MS (ESI): mass calcd. for C₂₂H₂₉F₃N₄O₂Si, 466.2; m/z found, 467.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J=2.3 Hz, 1H), 8.12-7.98 (m, 1H), 7.61-7.53 (m, 1H), 7.48-7.39 (m, 1H), 6.22 (s, 1H), 4.57 (s, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 0.76 (s, 9H), 0.82-0.70 (m, 6H).

Step B: 7-((5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. Thionyl chloride (3.03 mL, 41.8 mmol) was added to a solution of (44(tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (15 g, 32 mmol) and 2,6-di-tert-butylpyridine (14 ml, 64 mmol) in DCM (160 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO₃, then extracted twice with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (11.6 g, 74% yield). MS (ESI): mass calcd. for C₂₂H₂₈ClF₃N₄OSi, 484.2; m/z found, 485.2 [M+H]⁺.

Step C: Methyl 3-(54(tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (23.7 ml, 117 mmol) was added to a solution of 7-((5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (11.6 g, 23.9 mmol) in DCM (119 ml). Indium(III) bromide (2.6 g, 7.3 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was filtered, concentrated and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (5.0 g, 40% yield). MS (ESI): mass calcd. for C₂₇H₃₇F₃N₄O₃Si, 550.3; m/z found, 551.3 [M+H]⁺.

Step D: Methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Tetrabutylammonium fluoride (1 M in THF, 27 ml, 27 mmol) was added to a solution of methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (5.0 g, 9.1 mmol) in THF (50 ml). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH₄Cl, then extracted twice with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, concentrated, purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) and further purified by preparative acidic HPLC (0.05% TFA in water, 0.05% TFA in acetonitrile) to provide the title compound (3.8 g, 96% yield). MS (ESI): mass calcd. for C₂₁H₂₃F₃N₄O₃, 436.2; m/z found, 437.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J=2.1 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.19 (d, J=7.4 Hz, 1H), 4.90 (s, 1H), 4.74 (s, 2H), 3.63 (s, 3H), 2.71 (s, 3H), 2.64 (s, 3H), 1.37 (d, J=19.6 Hz, 6H).

Intermediate 170: Methyl (*S)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: (4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol n-Butyllithium (2.0 M, 3.1 ml, 6.2 mmol) was added dropwise to a stirring solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridine (Intermediate 47, 2.0 g, 6.3 mmol) in THF (14 ml) at −78° C. under nitrogen. The reaction was stirred at −78° C. for 2 minutes. A solution 3-(trifluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (Intermediate 28, 1.2 g, 5.1 mmol) in THF (10 ml) was added to the lithiate reaction mixture dropwise. The reaction was stirred at −78° C. for 5 minutes. The reaction was quenched with saturated aqueous NaHCO₃, and then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.0 g, 42%). MS (ESI): mass calcd. for C₂₂H₂₉F₃N₄O₂Si, 466.2; m/z found, 467.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (t, J=0.8 Hz, 1H), 8.05-7.99 (m, 1H), 7.25 (s, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.19 (s, 1H), 5.94 (s, 1H), 4.65 (dd, J=15.6, 1.1 Hz, 1H), 4.60 (dd, J=15.6, 1.0 Hz, 1H), 2.86 (s, 3H), 2.20 (s, 3H), 2.06 (s, 1H), 1.27 (t, J=7.1 Hz, 1H), 0.78 (s, 9H), 0.84-0.72 (m, 1H), 0.05 (s, 3H).

Step B: 7-((4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. Thionyl chloride (0.3 mL, 4.2 mmol) was added to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (1.5 g, 3.2 mmol) and 2,6-di-tert-butylpyridine (1.4 ml, 6.4 mmol) in DCM (16 mL). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.0 g, 64% yield). MS (ESI): mass calcd. for C₂₂H₂₈ClF₃N₄OSi, 484.2; m/z found, 485.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (t, J=0.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.62 (s, 1H), 7.25 (d, J=7.3 Hz, 1H), 6.35 (s, 1H), 4.58 (d, J=1.0 Hz, 2H), 3.98 (q, J=7.1 Hz, 1H), 2.71 (d, J=0.7 Hz, 3H), 2.08 (s, 3H), 1.12 (t, J=7.1 Hz, 1H), 0.80 (s, 9H), 0.86-0.74 (m, 1H), 0.05 (s, 3H).

Step C: Methyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (6.1 ml, 30 mmol) was added to a solution of 7-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (3.0 g, 6.2 mmol) in DCM (31 ml). Indium(III) bromide (0.67 g, 1.9 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was filtered, concentrated and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (0.5 g, 15% yield). MS (ESI): mass calcd. for C₂₇H₃₇F₃N₄O₃Si, 550.2; m/z found, 551.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.22 (d, J=0.8 Hz, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.06 (s, 1H), 5.04 (s, 1H), 4.60-4.49 (m, 2H), 3.59 (s, 3H), 2.86 (s, 3H), 2.11 (s, 3H), 2.01 (s, 1H), 1.28 (s, 3H), 1.22 (t, J=7.1 Hz, 1H), 0.74 (s, 9H), 0.76-0.70 (m, 1H), 0.14-0.07 (m, 6H).

Step D: Methyl 3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Tetrabutylammonium fluoride (1 M in THF, 1.4 ml, 1.4 mmol) was added to a solution of Methyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (0.5 g, 0.9 mmol) in THF (5 ml). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NH₄Cl, then extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, concentrated to and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (280 mg, 71% yield). This racemic mixture was used in the preparation of Example 587 and is designated as Intermediate 170-racemic. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₄O₃, 436.2; m/z found, 437.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=0.8 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.23 (s, 1H), 5.00 (s, 1H), 4.71-4.66 (m, 2H), 3.60 (s, 4H), 2.86-2.82 (m, 3H), 2.19 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

Step E: The mixture of (R/S)-methyl 3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.5 g) was separated by chiral SFC (stationary phase: ADH 2*25 cm, Mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The second eluting isomer, designated (*R), was not isolated. The first eluting isomer (573 mg) was designated (*S): MS (ESI): mass calcd. for C₂₁H₂₃F₃N₄O₃, 436.2; m/z found, 437.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=0.8 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.23 (s, 1H), 5.00 (s, 1H), 4.71-4.66 (m, 2H), 3.60 (s, 4H), 2.86-2.82 (m, 3H), 2.19 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

Intermediate 171: Methyl (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate

Step A: (4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. n-Butyllithium (1.6 M, 5.0 ml, 7.9 mmol) was added dropwise to a stirring solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridine (Intermediate 47, 1.7 g, 5.3 mmol) in THF (11 ml) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 2 minutes. A solution 1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (Intermediate 22, 1.0 g, 5.3 mmol) in THF (10 ml) was added to the lithiate reaction mixture dropwise. The reaction was stirred at −78° C. for 5 minutes. The reaction was quenched with saturated aqueous NaHCO₃, and then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.2 g, 53%). MS (ESI): mass calcd. for C₂₃H₃₄N₄O₂Si, 426.2; m/z found, 427.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.20 (s, 1H), 6.30 (s, 1H), 5.78 (s, 1H), 4.81-4.60 (m, 4H), 2.98 (s, 3H), 2.27 (s, 3H), 1.68 (t, J=7.3 Hz, 3H), 0.82 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H).

Step B: Methyl 3-(44(tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Trichloroacetonitrile (0.7 mL, 7.3 mmol) and DBU (63 mL, 0.4 mmol) were added to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (1.2 g, 2.8 mmol) in ACN (14 ml). The reaction was stirred at room temperature under nitrogen for 1 hour. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.1 mL, 5.6 mmol) was then added to the reaction, followed by trifluoromethanesulfonamide (0.4 g, 1.4 mmol), and the reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound as an impure mixture that was carried forward without further purification (1.3 g, 90% yield). MS (ESI): mass calcd. for C₂₈H₄₂N₄O₃Si, 510.3; m/z found, 511.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.02 (s, 1H), 5.28 (s, 1H), 4.69 (qd, J=7.2, 2.1 Hz, 2H), 4.67-4.51 (m, 2H), 4.16 (q, J=7.1 Hz, 0H), 3.65 (s, 3H), 3.00 (s, 3H), 2.17 (s, 3H), 1.64 (t, J=7.3 Hz, 3H), 1.27 (s, 6H), 0.73 (s, 9H), 0.01 (s, 3H), −0.06 (s, 3H).

Step C: Methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 5.1 ml, 5.1 mmol) was added to a solution of methyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (1.3 g, 2.5 mmol) in THF (28 ml) and 3 drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure. The material was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (0.6 g, 56% yield). MS (ESI): mass calcd. for C₂₂H₂₈N₄O₃, 396.2; m/z found, 397.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 6.98 (s, 1H), 5.05 (s, 1H), 4.57-4.44 (m, 4H), 3.48 (s, 3H), 3.26 (s, 1H), 2.77 (s, 3H), 2.08 (s, 3H), 1.48 (t, J=7.3 Hz, 3H), 1.32 (s, 3H), 1.13 (s, 3H).

Step D: The mixture of (R/S)-methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (590 mg) was purified and separated by chiral SFC (stationary phase: OD-H 2*25 cm, Mobile phase: 65% CO₂, 35% iPrOH, 0.1% DEA, stationary phase: IG 2*25 cm, Mobile phase: 70% CO₂, 30% EtOH, 0.1% DEA) to afford two enantiomers. The first eluting isomer (269 mg) was designated (*S): MS (ESI): mass calcd. for C₂₂H₂₈N₄O₃, 396.2; m/z found, 397.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.16 (s, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.98 (s, 1H), 5.06 (s, 1H), 4.57-4.43 (m, 4H), 3.48 (s, 3H), 2.80 (s, 3H), 2.08 (s, 3H), 1.47 (t, J=7.3 Hz, 3H), 1.32 (d, J=3.9 Hz, 3H), 1.13 (d, J=5.7 Hz, 3H).

Intermediate 172: Ethyl (*R)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: Ethyl (E)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. 7-Bromo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24, 7.0 g, 25 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (7.35 g, 32.5 mmol), and Na₂CO₃ (7.95 g, 75.0 mmol) were added to a 250-mL, three-necked round-bottom flask and then 1,4-dioxane (75 mL) and water (15 mL) were added. The mixture was sparged with nitrogen for 5 minutes and Pd(dppf)Cl₂ (1.83 g, 2.50 mmol) was added. The mixture was sparged with nitrogen for another 5 minutes and then stirred at 90° C. After 16 hours, the mixture was allowed to cool to room temperature. Water (100 mL) was added and the mixture was extracted numerous times with ethyl acetate which resulted in many organic fractions. The fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate 20:1 to 5:1) to give the title compound (7.0 g, 76%) as a brown solid. MS (ESI): mass calcd. for C₁₃H₁₂F₃N₃O₂, 299.1; m/z found, 299.9 [M+H]⁺.

Step B: Ethyl (E)-3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. (E)-Ethyl 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (6.8 g, 23 mmol), 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (Intermediate 46, 9.34 g, 29.5 mmol), DIPEA (8.81 g, 68.2 mmol), and 1,4-dioxane (80 mL) were added to a 250-mL round-bottomed flask. The mixture was sparged with nitrogen for 5 minutes and then Pd(t-Bu₃P)₂ (1.16 g, 2.27 mmol) was added. The mixture was stirred at 125° C. After 16 h, the mixture was allowed to cool to room temperature. The suspension was filtered and the filter cake washed with ethyl acetate (80 mL). The filtrate was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate 10:1 to 2:1) to give the title compound (6.0 g, 49%) as a brown solid. MS (ESI): mass calcd. for C₂₆H₃₃F₃N₄O₃Si, 534.2; m/z found, 535.1 [M+H]⁺.

Step C: Ethyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Raney nickel (5.0 g, in water) was added to a solution of ethyl (E)-3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (6.0 g, 11 mmol) in EtOH (60 mL). The reaction mixture was stirred under a hydrogen atmosphere (15 Psi) at room temperature. After 16 hours, the mixture was filtered through a pad of Celite® and the pad was washed with ethyl acetate (60 mL). The filtrate was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title product (5.2 g) as an oil which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₆H₃₅F₃N₄O₃Si, 536.2; m/z found, 537.1 [M+H]⁺.

Step D: Ethyl (*S)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. TFA (6 mL) and ethyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (5.2 g) were added to a 100-mL, round-bottomed flask. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Aqueous NaHCO₃(60 mL) was added to the residue and the mixture was extracted with ethyl acetate which resulted in numerous organic fractions. These fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the product (4.6 g) as an oil. This material was combined with a second batch (2 g) made in a similar manner as above. This material was purified by preparative HPLC using a Phenomenex Gemini 250 mm×50 mm column (10 μm, eluent: 10% to 45% (v/v) CH₃CN in water with 0.05% v/v added ammonia). The pure fractions were combined and concentrated under reduced pressure. The residue was suspended in water (10 mL), frozen and lyophilized to afford the title compound (4.3 g, 51%) as a sticky oil. This racemic mixture was further purified by chiral SFC (AD column, 250 mm×50 mm, 10 μm, EtOH—CO₂ containing 0.1% of 25% aq. NH₃) to afford two enantiomers. The first eluting isomer (1.62 g) was designated *R: MS (ESI): mass calcd. for C₂₀H₂₁F₃N₄O₃, 422.2; m/z found, 423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=7.3 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.27 (d, J=7.3 Hz, 1H), 5.22 (t, J=5.3 Hz, 1H), 4.89 (t, J=7.9 Hz, 1H), 4.45 (d, J=5.1 Hz, 2H), 4.02-3.94 (m, 2H), 3.28 (d, J=7.9 Hz, 2H), 2.75 (s, 3H), 2.36 (s, 3H), 1.07 (t, J=7.2 Hz, 3H).

Intermediate 173: Ethyl (*S)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The second eluting isomer (1.72 g) from the chiral separation described in Intermediate 172 was designated *S: MS (ESI): mass calcd. for C₂₀H₂₁F₃N₄O₃, 422.2; m/z found, 423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=7.1 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.22 (t, J=5.3 Hz, 1H), 4.88 (t, J=7.8 Hz, 1H), 4.45 (d, J=5.3 Hz, 2H), 4.02-3.93 (m, 2H), 3.27 (d, J=7.9 Hz, 2H), 2.75 (s, 3H), 2.35 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).

Intermediate 174: Ethyl (E)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)acrylate

Step A: N,6-Dimethylpyridazin-3-amine. A 5-L pressure tank reactor was charged with 3-chloro-6-methylpyridazine (75 g, 580 mmol) and a 30% solution of methylamine in methanol (1.5 L). The resulting solution was stirred overnight at 110° C. The mixture was cooled and then concentrated under reduced pressure. The residue was purified by flash column chromatography (10:1 dichloromethane:methanol) to provide the title compound as a light yellow solid (55 g, 77%).

Step B: 4-Bromo-N,6-dimethylpyridazin-3-amine. A 1-L, round-bottom flask was charged with N,6-Dimethylpyridazin-3-amine (36 g, 290 mmol) and acetic acid (400 mL). This was followed by the dropwise addition of bromine (141 g, 880 mmol). The resulting solution was stirred overnight at 65° C. The solution was cooled and then diluted with dichloromethane (1.5 L). The pH of the solution was adjusted to 8-9 by adding aqueous ammonia solution (˜800 mL). The resulting mixture was washed sequentially with aqueous Na₂SO₃ solution (600 mL) and water (600 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound (7.9 g, 13%) as a yellow solid.

Step C: 4-(3,3-Diethoxyprop-1-yn-1-yl)-N,6-dimethylpyridazin-3-amine. A 250-mL, round-bottom flask was purged with nitrogen and then charged with 4-bromo-N,6-dimethylpyridazin-3-amine (7.9 g, 39 mmol), 3,3-diethoxyprop-1-yne (6.0 g, 47 mmol), CuI (740 mg, 3.9 mmol), triethylamine (5.9 g, 58 mmol), Pd(PPh₃)₂Cl₂ (5.5 g, 7.8 mmol), and THF (80 mL). The resulting solution was stirred for 1.5 h at 65° C. The mixture was cooled and the solids removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (petroleum ether-ethyl acetate) to provide the title compound (7.7 g, 79%) as a yellow solid.

Step D: 6-(Diethoxymethyl)-3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine. A 500-mL, round-bottom flask was charged with 4-(3,3-diethoxyprop-1-yn-1-yl)-N,6-dimethylpyridazin-3-amine (7.7 g, 31 mmol) and a solution of TBAF in tetrahydrofuran (1 M, 230 mL). The resulting solution was stirred overnight at 65° C. The mixture was cooled and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and then washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate, 2:1) to provide the title compound (3.8 g, 49%) as a brown oil.

Step E: 3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-carbaldehyde. A 250-mL, 3-necked round bottom flask was charged with a solution of 6-(diethoxymethyl)-3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine (3.8 g, 15 mmol) in 1,4-dioxane (40 mL). This was followed by the addition of hydrogen chloride (40 mL, 6 N) dropwise at 0° C. The resulting solution was stirred for 2 h at room temperature and then water (100 mL) was added. The layers were separated and the aqueous washed with ethyl acetate. The pH of the aqueous layer was adjusted to 8-9 by addition of aqueous sodium bicarbonate solution. The basic solution was extracted with ethyl acetate which resulted in numerous organic layers which were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a yellow solid (2.2 g) which was used in the next step without purification.

Step F: Ethyl (E)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)acrylate. A 250-mL, 3-necked round bottom flask was charged with NaH (60% dispersion in oil, 0.6 g) and THF (10 mL) at 0° C. A solution of ethyl(diethoxyphosphoryl) acetate (3.4 g, 15 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 0.5 h. A solution of 3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-carbaldehyde (2.2 g, 13 mmol) in THF (30 mL) was added dropwise. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was quenched by addition of 5% aqueous NH₄Cl solution (200 mL) at 0° C. After warming to RT, the mixture was extracted with ethyl acetate which resulted in numerous organic layers which were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate, 2:1) to provide the title compound (2.0 g, 66%) as a light-yellow solid. MS (ESI): mass calcd. for C₁₃H₁₅N₃O₂, 245.1; m/z found, 246.2 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=16.2 Hz, 1H), 7.46 (s, 1H), 6.74 (s, 1H), 6.67 (d, J=15.9 Hz, 1H), 4.36-4.28 (m, 2H), 4.10 (s, 3H), 2.80 (s, 3H), 1.37 (t, J=6.9 Hz, 3H).

Intermediate 175: Methyl (2*S, 3*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: Ethyl (*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. TBDPSCl (3.33 mL, 12.8 mmol) was added to a solution consisting of ethyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 27, 3.6 g, 8.5 mmol), 1H-imidazole (1.75 g, 25.7 mmol), and dichloromethane (50 mL). The mixture was stirred at room-temperature for 20 minutes which resulted in a suspension. The suspension was filtered through a pad of Celite® and the pad washed with ethyl acetate (20 mL). The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash column chromatography (petroleum ether-ethyl acetate, 50:1 to 5:1) to provide the title compound (5.2 g, 92%) as a white solid. MS (ESI): mass calcd. for C₃₇H₄₀F₃N₃O₃Si, 659.3; m/z found, 660.3 [M+H]⁺.

Step B: (*R)-3-(3-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Lithium hydroxide monohydrate (378 mg, 9.01 mmol) was added to a solution consisting of ethyl (*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (3.3 g, 5.0 mmol), EtOH (12 mL), and H₂O (3 mL). The mixture was stirred at room temperature for 2 hours. The pH was adjusted to 5 by the addition of 1 M aqueous HCl solution and then diluted with H₂O (30 mL). The mixture was extracted with ethyl acetate which resulted in numerous organic layers which were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (3.0 g, 88%) as a white solid. MS (ESI): mass calcd. for C₃₅H₃₆F₃N₃O₃Si, 631.3; m/z found, 632.3 [M+H]⁺.

Step C: (R)-4-Benzyl-3-((*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoyl)oxazolidin-2-one. CDI (385 mg, 2.37 mmol) was added to a solution consisting of (*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (1.0 g, 1.6 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 6 hours. Tetrahydrofuran was allowed to evaporate with a stream of nitrogen and the residue was diluted with acetonitrile (10 mL). (R)-4-benzyloxazolidin-2-one (309 mg, 1.74 mmol) and DBU (47 μL, 0.31 mmol) were added to the mixture. After 16 hours, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate, 1:0 to 3:1) to afford the title compound (860 mg, 68%) as a white solid. MS (ESI): mass calcd. for C₄₅H₄₅F₃N₄O₄Si, 790.3; m/z found, 791.3 [M+H]⁺.

Step D: (4R)-4-Benzyl-3-((3*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoyl)oxazolidin-2-one. KHMDS (759 μL, 1 M in THF, 0.759 mmol) was added to a solution consisting of (R)-4-benzyl-3-((*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoyl)oxazolidin-2-one (500 mg, 0.632 mmol) and tetrahydrofuran (5 mL) at 78° C. The reaction mixture was stirred at 78° C. for 1.5 hours before adding iodomethane (449 mg, 3.16 mmol). The reaction mixture was stirred 78° C. for 4 hours before quenching with saturated aqueous NH₄Cl solution (0.5 mL) at 78° C. The mixture was allowed to warm to room temperature and then water (30 mL) was added. The mixture was extracted with ethyl acetate which resulted in numerous organic layers which were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate, 1:0 to 3:1) to provide the title compound as a mixture of diastereoisomers (420 mg, 83%) as a white solid. MS (ESI): mass calcd. for C₄₆H₄₇F₃N₄O₄Si, 804.3; m/z found, 805.3 [M+H]⁺.

Step E: (3*R)-3-(3-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Hydrogen peroxide (275 mg, 2.43 mmol) and lithium hydroxide monohydrate (969 μL, 1 M in water, 0.969 mmol) were added to a 0° C. solution of (4R)-4-benzyl-3-((3*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoyl)oxazolidin-2-one (390 mg, 0.484 mmol) in THF (8 mL) and H₂O (1.2 mL). The mixture was stirred at room temperature for 26 hours before quenching with saturated aqueous Na₂SO₃ solution (0.6 mL). The mixture was concentrated under reduced pressure and then diluted with water (20 mL). The pH was adjusted to 5 by adding 1 M aqueous HCl solution. The mixture was extracted with ethyl acetate which resulted in numerous organic layers which were combined, washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (330 mg) as a colorless oil which was used in the next step without purification. MS (ESI): mass calcd. for C₃₆H₃₈F₃N₃O₃Si, 645.3; m/z found, 646.3 [M+H]⁺.

Step F: Methyl (3*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. (Diazomethyl)trimethylsilane (0.50 mL, 2M in hexane, 1.0 mmol) was added drop-wise to a solution of (3*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (320 mg, 0.496 mmol) in dichloromethane (8 mL) and methanol (4 mL) at room temperature. The reaction mixture was stirred for 6 hours and then TFA (0.1 mL) was added. The mixture was concentrated to dryness under reduced pressure and then dichloromethane (80 mL) was added. The mixture was washed with saturated aqueous NaHCO₃ solution (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate, 10:0 to 1:1) to provide the title compound (160 mg) as a white solid. MS (ESI): mass calcd. for C₃₇H₄₀F₃N₃O₃Si, 659.3; m/z found, 660.2 [M+H]⁺.

Step G: Methyl (2*S,3*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. TBAF (0.29 mL, 1 M in THF, 0.29 mmol) was added to a solution of methyl (3*R)-3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (160 mg, 0.242 mmol) in THF (5 mL) at room temperature. After 6 hours, the reaction mixture was concentrated under reduced pressure and then ethyl acetate (90 mL) was added. The resulting mixture was washed with water (30 mL), brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether-ethyl acetate, 10:0 to 1:1) to provide the title compound as a mixture of isomers (102 mg) as a white solid. MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.1 [M+H]⁺. The title compound was further purified chiral SFC (stationary phase: Chiralpak AD, 250 mm×30 mm, 5 μm isocratic mobile phase: 25% CO₂, 75% MeOH with 0.1% aqueous NH₃) to afford two diastereoisomers. The first eluting isomer (50.1 mg) was designated (*S): MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=7.2 Hz, 1H), 7.29 (s, 1H), 7.15-7.06 (m, 2H), 6.96 (d, J=7.2 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H), 4.64 (s, 2H), 3.57 (s, 3H), 3.42-3.33 (m, 1H), 2.89 (s, 3H), 2.25 (s, 3H), 1.15 (d, J=7.2 Hz, 3H).

Intermediate 176: Methyl (2*R, 3*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The second eluting isomer (81.1 mg) from the chiral SFC separation described in Intermediate 175 was designated (*R): MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=7.2 Hz, 1H), 7.31 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.13 (s, 2H), 4.69 (d, J=4.4 Hz, 2H), 4.50 (d, J=11.6 Hz, 1H), 3.53 (s, 3H), 3.46-3.33 (m, 1H), 2.83 (s, 3H), 2.28 (s, 3H), 1.79-1.73 (m, 1H), 1.24 (d, J=6.4 Hz, 3H).

Intermediate 177: 7′-(2-(3-fluoroazetidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (54 mg, 15%) was prepared using analogous conditions as described in Intermediate 127 where 7′-chloro-8′methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) was used instead of 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 67) and 2-(3-fluoroazetidin-1yl)ethan-1-ol was used instead of 2-(piperidin-1-yl)ethan-1-ol. MS (ESI): mass calcd. for C₁₅H₂₀FN₃O₄S 357.1, m/z found 358.2 [M+H]⁺.

Intermediate 178: 8′-methyl-7′-((2-morpholinoethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (510 mg, 95%) was prepared using analogous conditions as described in Intermediate 127 where 7′-chloro-8′methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) was used instead of 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 67) and 2-morpholinoethan-1-ol was used instead of 2-(piperidin-1-yl)ethan-1-ol. MS (ESI): mass calcd. for C₁₆H₂₃N₃O₅S 369.1, m/z found 370.1 [M+H]⁺.

Intermediate 179: 7′-(2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (234 mg, 36%) was prepared using analogous conditions as described in Intermediate 25 where 2-(pyrolidin-1-yl)ethan-1-ol was used instead of 2-(piperidin-1-yl)ethan-1-ol MS (ESI): mass calcd. for C₁₅H₂₁N₃O₄S 339.1, m/z found 340.2 [M+H]⁺.

Intermediate 180: tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5 [oxathiazepin]-7′-yl)propanoate

Step A: (E)-tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)acrylate. tert-Butyl acrylate (477 mg, 3.72 mmol), Pd(OAc)₂ (32.1 mg, 0.143 mmol), 2-(di-tert-butylphosphino)biphenyl (85.5 mg, 0.287 mmol), and Et₃N (580 mg, 5.73 mmol) were added to a solution of 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (1.00 g, 2.86 mmol, Intermediate 124) and DMF (18 mL). The resulting mixture was sparged with N₂ for 5 minutes and then stirred while heating at 120° C. for 3 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with aqueous saturated NH₄Cl solution (7 mL) and the resulting mixture extracted with ethyl acetate (2×). These extractions resulted in several fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:5, gradient) to afford the title compound (805 mg, 71%) as a yellow solid. MS (ESI): mass calcd. for C₁₈H₂₄N₂O₆S 396.1 m/z found 396.9 [M+H]⁺.

Step B: tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate. (E)-tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)acrylate (805 mg, 2.03 mmol), MeOH (10 mL), and dry Pd/C (200 mg, 10 wt. %, 0.189 mmol) were added to 75 mL hydrogenation bottle and stirred at room temperature for 16 hours under H₂ (50 psi). The suspension was filtered through a pad of Celite® and the pad was washed with MeOH (20 mL).

The filtrate was concentrated to dryness under reduced pressure to give the product, which was combined with another batch of tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate and purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:5, gradient) to afford the title compound (781 mg). MS (ESI): mass calcd. for C₁₈E126N₂O₆S 398.2 m/z found 399.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60-8.10 (m, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 3.81 (t, J=9.8 Hz, 2H), 3.57 (d, J=10.8 Hz, 2H), 3.47 (s, 2H), 2.97 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H), 1.72-1.46 (m, 4H), 1.34 (s, 9H).

Intermediate 181: 8′-methyl-7′-((1-(piperidin-1-yl)propan-2-yl)oxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (230 mg, 79%) was prepared using analogous conditions as described in Intermediate 72 where 1-(piperidin-1-yl)propan-2-ol was used instead of 2-(pyrrolidin-1-yl)ethanol in step C. MS (ESI): mass calcd. for C₂₀H₃₁N₃O₅S 425.2 m/z found 426.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (t, J=6.8 Hz, 1H), 7.82 (d, J=1.0 Hz, 1H), 5.33-5.25 (m, 1H), 3.89-3.76 (m, 2H), 3.66-3.61 (m, 2H), 3.50-3.38 (m, 2H), 2.62-2.56 (m, 1H), 2.50-2.35 (m, 5H), 2.11 (s, 3H), 1.65-1.55 (m, 4H), 1.50-1.42 (m, 4H), 1.39-1.26 (m, 5H).

Intermediate 182: 7′-(2-azetidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (214 mg, 32%) was prepared using analogous conditions as described in Intermediate 127 where 7′-chloro-8′methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131) was used instead of 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 67) and 2-(azetidin-1yl)ethan-1-ol was used instead of 2-(piperidin-1-yl)ethan-1-ol. MS (ESI): mass calcd. for C₁₅H₂₁N₃O₄S 339.1, m/z found 340.2 [M+H]⁺.

Intermediate 183: 7′-(2-hydroxyethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 7′-((2-(Benzyloxy)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. Sodium hydride in mineral oil (860 mg, 60% purity, 21.5 mmol) was added in portions to a solution of 2-(benzyloxy)ethanol (2.6 g, 17 mmol) in toluene (30 mL) at 0° C. The resulting mixture was stirred for 0.5 hours with gradual warming to room-temperature and then treated with 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (3.0 g, 8.6 mmol, Intermediate 124), o-tol-BiNAP (230 mg, 0.339 mmol), and Pd₂(dba)₃ (160 mg, 0.175 mmol). The resulting mixture was stirred at 100° C. for 16 hours before cooling to room-temperature and quenching the excess NaH with acetic acid (1.3 mL) to pH 6. The suspension was filtered through a pad of Celite® and the pad washed with ethyl acetate (50 mL). The filtrate was concentrated to dryness under reduced pressure and the resulting residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:2, gradient) to afford the title compound (2.5 g, 58%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₀H₂₄N₂O₆S 420.1 m/z found 443.1 [M+Na]⁺.

Step B: 7′-((2-hydroxyethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. Dry Pd/C (300 mg, 10%) was added to a solution of 7′-((2-(benzyloxy)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (2.5 g) and THF (50 mL). The resulting mixture was stirred at room temperature for 12 hours under 50 psi of hydrogen. The suspension was filtered through a pad of Celite® and the pad washed with THF (50 mL). The filtrate was concentrated to dryness under reduced pressure to give the still-impure product (2.0 g), which was triturated with 10:1 petroleum ether/ethyl acetate (30 mL) and the resulting suspension isolated via filtration. The filter cake was washed with petroleum ether (20 mL) and dried under reduced pressure to afford the title compound (1.7 g, 85%). MS (ESI): mass calcd. for C₁₃H₁₈N₂O₆S 330.1 m/z found 331.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25-8.15 (m, 1H), 8.00-7.92 (m, 1H), 6.71 (d, J=8.4 Hz, 1H), 4.89 (t, J=5.6 Hz, 1H), 4.27 (t, J=4.8 Hz, 2H), 3.83-3.74 (m, 2H), 3.72-3.67 (m, 2H), 3.65-3.56 (m, 2H), 3.48-3.41 (m, 2H), 1.68-1.53 (m, 4H).

Intermediate 184: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

Step A: (34(Tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. N-butyllithium (2.5 M, 4.8 ml, 12 mmol) was added dropwise to a stirring solution of 5-bromo-1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 29, 3.0 g, 12 mmol) in THF (50 ml) in a dry ice/acetone bath under nitrogen. 3(((Tert-butyldimethylsilyl)oxy)methyl)-4-methylbenzaldehyde (Intermediate 163, 3.2 g, 12 mmol) was dissolved in THF (7 ml) and the resulting solution was added to the lithiate reaction dropwise. The reaction was then removed from the dry ice/acetone bath and allowed to warm to room temperature for 3 hours. The reaction was quenched with saturated aqueous NH₄Cl. Brine and EtOAc were added and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, washed with brine, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-20% EtOAc/hexanes) to provide the title compound (2.46 g, 47% yield). MS (ESI): mass calcd. for C₂₅H₃₅N₃O₂Si, 437.2; m/z found, 438.3 [M+H]⁺.

Step B: Methyl 3-(34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Trichloroacetonitrile (2 ml, 20 mmol) and DBU (0.3 ml, 2 mmol) were added to a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (4.24 g, 9.69 mmol) in ACN (50 ml). The reaction was stirred at room temperature under nitrogen for 50 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (10 ml, 49 mmol) was then added to the reaction, followed by trifluoromethanesulfonamide (2.72 g, 9.69 mmol), and the reaction was stirred at room temperature under nitrogen for 45 minutes. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-20% EtOAc/DCM) to provide the title compound (4.82 g, 95% yield). MS (ESI): mass calcd. for C₃₀H₄₃N₃O₃Si, 521.3; m/z found, 522.3 [M+H]⁺.

Step C: Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. Tetrabutylammonium fluoride (1 M in THF, 18 ml, 18 mmol) was added to a solution of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (4.82 g, 9.24 mmol) in THF (92 ml). The reaction was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure. The material was purified by flash column chromatography (0-100% EtOAc/hexanes) to provide the title compound (4.84 g, 128% yield) containing TBAF as an impurity. MS (ESI): mass calcd. for C₂₄H₂₉N₃O₃, 407.2; m/z found, 408.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.12-7.08 (m, 1H), 7.03-6.97 (m, 1H), 6.97-6.92 (m, 1H), 4.76 (s, 1H), 4.51 (s, 2H), 3.66-3.57 (m, 1H), 3.39 (s, 3H), 2.70 (s, 3H), 2.18 (s, 3H), 1.30 (s, 3H), 1.27-1.22 (m, 2H), 1.21 (s, 3H), 1.19-1.13 (m, 2H).

Step D: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Thionyl chloride (0.7 mL, 9.6 mmol) was added to a solution of methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (1.87 g, 4.59 mmol) in DCM (23 mL). The reaction was stirred at room temperature for 40 minutes. The reaction was quenched with saturated aqueous NaHCO₃, the resulting biphasic mixture was separated, and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure to provide the title compound without further purification (1.8 g, 92% yield). MS (ESI): mass calcd. for C₂₄H₂₈ClN₃O₂, 425.2; m/z found, 426.2 [M+H]⁺.

Intermediate 185: Methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: (54(Tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. N-butyllithium (1.6 M, 7.8 ml, 12.5 mmol) was added dropwise to a stirring solution of 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (Intermediate 46, 4.0 g, 13 mmol) in THF (47 ml) in a dry ice/acetone bath under nitrogen. 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridine-7-carbaldehyde (Intermediate 28, 2.35 g, 10.3 mmol) was dissolved in THF (47 ml) added to the lithiate reaction dropwise. The reaction was stirred for 5 minutes, then quenched with saturated aqueous NH₄Cl and extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (EtOAc/hexanes) to provide the title compound (3 g, 63% yield). This procedure was repeated five times, to yield a total of 15 g of the title compound. MS (ESI): mass calcd. for C₂₂H₂₉F₃N₄O₂Si, 466.2; m/z found, 467.2 [M+H]⁺.

Step B: 7454(Tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. Thionyl chloride (3 mL, 41 mmol) was added to a solution of (5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (15 g, 32 mmol) and 2,6-di-tert-butylpyridine (14 ml, 62 mmol) in DCM (160 mL). The reaction was stirred at room temperature for 5 minutes. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-100% ethyl acetate/hexanes) to provide the title compound (11.6 g, 74% yield). MS (ESI): mass calcd. for C₂₂H₂₈ClF₃N₄OSi, 484.2; m/z found, 485.2 [M+H]⁺.

Step C: Methyl 3-(54(tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (24 ml, 118 mmol) was added to a solution of 7-((5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (11.6 g, 24 mmol) in DCM (118 ml). Indium(III) bromide (2.6 g, 7.3 mmol) was added and the reaction was stirred at room temperature for 16 hours. Saturated aqueous NaHCO₃ was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (5 g, 38% yield) without further purification. MS (ESI): mass calcd. for C₂₇H₃₇F₃N₄O₃Si, 550.2; m/z found, 551.3 [M+H]⁺.

Step D: Methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Tetrabutylammonium fluoride (1 M in THF, 27 ml, 27 mmol) was added to a solution of methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (5 g, 9 mmol) in THF (50 ml). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO₃, the resulting biphasic mixture was separated, and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-100% ethyl acetate/hexanes) to provide the title compound (3.8 g, 96% yield). MS (ESI): mass calcd. for C₂₁H₂₃F₃N₄O₃, 436.2; m/z found, 437.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) □ 8.60 (d, J=2.1 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.19 (d, J=7.4 Hz, 1H), 4.90 (s, 1H), 4.74 (s, 2H), 3.63 (s, 3H), 2.71 (s, 3H), 2.64 (s, 3H), 1.37 (d, J=19.6 Hz, 6H).

Intermediate 186: Methyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

The second eluting isomer (1.9 g) from the chiral separation described in Intermediate 184 was designated (*R): MS (ESI): mass calcd. for C₂₄H₂₉N₃O₃, 407.2; m/z found, 408.2 [M+H]⁺.

Intermediate 187: 7′-(3-(3-Hydroxypropoxy)propoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 3-(Benzyloxy)propyl 4-methylbenzenesulfonate. 3-(Benzyloxy)propan-1-ol (10.0 g, 60.2 mmol), p-toluenesulfonyl chloride (17.2 g, 90.2 mmol), triethylamine (25.0 mL, 179 mmol), and dichloromethane (100 mL) were combined. The resultant mixture was stirred at 20° C. for 3 hours, then was poured into water (50 mL) and extracted with dichloromethane (50 mL×2). These organic solvent fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 5:1) to afford the title compound (18 g, 93%) as a brown oil, and was used in the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J=8.4 Hz, 2H), 7.38-7.22 (m, 7H), 4.40 (s, 2H), 4.19-4.14 (m, 2H), 3.50 (t, J=6.0 Hz, 2H), 2.42 (s, 3H), 1.98-1.90 (m, 2H).

Step B: 3-(3-(Benzyloxy)propoxy)propan-1-ol. Sodium hydride in mineral oil (6.0 g, 60% purity, 0.15 mmol) was added in portions to a 0° C. (ice/water) solution consisting of propane-1,3-diol (17.0 g, 223 mmol) and DMF (40 mL). The resultant mixture was stirred for 2 hours with gradual warming to room temperature and then treated with a solution consisting of 3-(benzyloxy)propyl 4-methylbenzenesulfonate (18.0 g, 56 mmol) and DMF (40 mL) at 0° C. The mixture was heated to 80° C. for 12 hours, then was cooled to room temperature, poured into saturated aqueous NH₄Cl (40 mL), and extracted with ethyl acetate (200 mL×2). These organic solvent fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 1:1) to afford the title compound (9 g, 71%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.25 (m, 4H), 4.49 (s, 2H), 3.78-3.71 (m, 2H), 3.71-3.66 (m, 1H), 3.59 (t, J=5.6 Hz, 2H), 3.54 (t, J=6.4 Hz, 4H), 2.05 (s, 2H), 1.92-1.82 (m, 4H).

Step C: 7′-(3-(3-(Benzyloxy)propoxy)propoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. Sodium hydride in mineral oil (460 mg, 60% purity, 11.5 mmol) was added in portions to a 0° C. (ice/water) solution consisting of 3-(3-(benzyloxy)propoxy)propan-1-ol (2.0 g, 8.9 mmol) and toluene (20 mL). The resultant mixture was stirred for 0.5 hours with gradual warming to room temperature and then treated with 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 124, 1.5 g, 4.3 mmol), o-tol-BINAP (130 mg, 0.192 mmol), and Pd₂(dba)₃ (80 mg, 0.087 mmol). The resultant mixture was stirred at 100° C. for 16 hours, then was quenched with acetic acid (0.7 mL) (adjusted pH of the mixture to 6). The resulting suspension was filtered through a pad of Celite® and the pad washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness under reduced pressure to give the product, which was combined with another batch of the same compound and then purified by FCC (eluent: petroleum ether/ethyl acetate=10:1 to 1:3) to afford the title compound (1.0 g) which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₄H₃₂N₂O₇S, 492.19; m/z found, 493.1 [M+H]⁺.

Step D: 7′-(3-(3-Hydroxypropoxy)propoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. 7′-(3-(3-(Benzyloxy)propoxy)propoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (1.0 g, 2 mmol), dry Pd/C (200 mg, 10%), and MeOH (20 mL) were added to a 100 mL hydrogenation bottle. The resultant mixture was stirred under H₂ (50 psi) at room temperature for 12 hours. The suspension was filtered through a pad of Celite® and the pad washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness under reduced pressure to afford the title product (850 mg, 104%, as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C₁₇H₂₆N₂O₇S, 402.15; m/z found, 403.0 [M+H]⁺.

Intermediate 188: Methyl (*S)-3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

Step A: (5-(((tert-Butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. n-BuLi (4.1 mL, 10 mmol) was slowly added drop-wise to a −65° C. solution of 5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyridine (3.0 g, 9.5 mmol, Intermediate 46) and THF (30 mL). The resulting mixture was stirred at −65° C. for 5 minutes before treating drop-wise with a solution of 1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (2.0 g, 10 mmol, Intermediate 56 step B) in THF (50 mL) at −65° C. The resulting mixture was stirred at −65° C. for 2 hours then poured into the sat. NH₄Cl (60 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were washed with brine (1×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 1:0 to 0:1; gradient) to afford the title compound (1.8 g, 42%). MS (ESI): mass calcd. for C₂₄H₃₄N₄O₂Si 438.3 m/z found 439.5 [M+H]⁺.

Step B: Methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. DBU (0.13 mL, 0.87 mmol) and 2,2,2-trichloroacetonitrile (0.8 mL, 8.0 mmol) were added to a mixture of (5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (1.6 g, 3.6 mmol) and MeCN (25 mL) under N₂ at room-temperature. The resulting mixture was stirred at room-temperature for 1 hour before treating with ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (3.2 g, 18 mmol) and a solution of Tf₂N (1.1 g, 3.9 mmol) in MeCN (5 mL). The mixture was stirred at room-temperature for 3 hours then treated with another batch of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.5 g, 8.6 mmol) and solution consisting of Tf₂N (500 mg, 1.78 mmol) in MeCN (3 mL). The resultant mixture was stirred at room-temperature for another 3 hours, quenched with sat. NaHCO₃(50 mL) and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate, 10:1 to 1:2; gradient) to yield the compound (1.7 g, 82%). MS (ESI): mass calcd. for C₂₉H₄₂N₄O₃Si 522.3 m/z found 523.6 [M+H]⁺.

Step C: Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate. TBAF (6.5 mL, 1M in THF, 6.5 mmol) was added to a solution of methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (1.7 g, 3.3 mmol), and THF (20 mL). The resulting mixture was stirred for 1.5 hours at room-temperature before pouring into water (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate, 100%) to afford the title compound (580 mg, 43%). MS (ESI): mass calcd. for C₂₃H₂₈N₄O₃ 408.22 m/z found 409.2 [M+H]⁺.

Step D: (*S) Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate. The mixture of methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate isomers were separated by chiral SFC (Stationary phase: Daicel Chiralpak AD 10 μm 150×50 mm, Mobile phase: (75% CO₂, 25% EtOH (w/0.1% 25% aqueous NH₃)) to afford two enantiomers. The first eluting isomer (9.5 g, 38%) was designated *S. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30-8.27 (m, 1H), 7.67-7.61 (m, 3H), 5.23 (t, J=5.3 Hz, 1H), 4.77 (s, 1H), 4.45-4.41 (m, 2H), 3.99-3.93 (m, 1H), 3.47 (s, 3H), 2.70 (s, 3H), 2.33 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.24-1.20 (m, 4H).

Step E: (*S)-Methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. SOCl₂ (0.52 mL, 7.2 mmol) was added to a solution of (*S) methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate (580 mg, 1.42 mmol) and dichloromethane (8.0 mL) under N₂. The resulting mixture was stirred at room-temperature for 1 hour before concentrating to dryness under reduced pressure to afford the product (600 mg) which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₃H₂₇ClN₄O₂426.2 m/z found 427.0 [M+H]⁺.

Intermediate 189: Methyl (*R)-3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate

Step A: (*R) Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate. The mixture of methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate isomers (Intermediate 188, step C) were separated by chiral SFC (Stationary phase: Daicel Chiralpak AD 10 μm 150×50 mm, Mobile phase: (75% CO₂, 25% EtOH (w/0.1% 25% aqueous NH₃)) to afford two enantiomers. The second eluting isomer (9.5 g, 38%) was designated *R. ¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.28 (m, 1H), 7.68-7.62 (m, 3H), 5.24 (t, J=5.3 Hz, 1H), 4.78 (s, 1H), 4.46-4.42 (m, 2H), 4.00-3.94 (m, 1H), 3.47 (s, 3H), 2.71 (s, 3H), 2.34 (s, 3H), 1.30 (s, 3H), 1.26 (s, 3H), 1.25-1.21 (m, 4H).

Step B: methyl (*R)-3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. The title compound (480 mg) was prepared using analogous conditions as described in Intermediate 188 where (*R) methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate was used instead of (*S) methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate in step E. MS (ESI): mass calcd. for C₂₃H₂₇ClN₄O₂ 426.2 m/z found 427.2 [M+H]⁺.

Intermediate 190: 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (23.5 g, 60%) was prepared using analogous conditions as described in Intermediate 59 where 2-chloro-5-methylpyridine-3-sulfonyl chloride was used instead of 2-chloropyridine-3-sulfonyl chloride in step C. MS (ESI): mass calcd. for C₁₀H₁₂N₂O₄S 256.1 m/z found 256.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J=1.8 Hz, 1H) 8.31 (br s, 1H) 8.00 (d, J=2.0 Hz, 1H) 4.35-4.49 (m, 4H) 3.83 (s, 2H) 2.35 (s, 3H).

Intermediate 191: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate

Step A: (4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. A 1.3 M solution of i-PrMgCl.LiCl in THF (30 mL, 39 mmol) was added dropwise to a stirring solution of 3-(difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 129, Step F, 10 g, 32 mmol) in THF (120 mL) at 10° C. After 1 hour, a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (Intermediate 147, 9.5 g, 36 mmol) in THF (30 mL) was added dropwise and then the mixture was allowed to warm to room temperature. After 16 hours, the mixture was poured into saturated aqueous NH₄Cl solution and then extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate=1:0 to 0:1) to provide the title compound as a yellow oil (7.5 g, 45%). MS (ESI): mass calcd. for C₂₂H₃₀F₂N₄O₂Si, 448.2; m/z found, 449.5 [M+H]⁺.

Step B: 7-((4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. SOCl₂ (1.1 mL, 15 mmol) was added drop-wise to a 100 mL, three-necked round-bottomed flask containing a icewater cooled solution of (44(tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (6.0 g, 12 mmol) and 2,6-di-tert-butylpyridine (6.8 mL, 29 mmol) in dichloromethane (80 mL). After 40 minutes, the mixture was brought to pH 8 by adding saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate=1:0 to 0:1) to provide the title compound as a yellow oil (5 g, 86%). MS (ESI): mass calcd. for C₂₂H₂₉ClF₂N₄OSi, 466.2; m/z found, 467.4 [M+H]⁺.

Step C: tert-Butyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. A mixture containing InBr₃ (1.9 g, 5.4 mmol), 7-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (5 g, 11 mmol), and ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (Intermediate 121, 23.0 g, 106 mmol) in dichloromethane (80 mL) was stirred at room temperature. After 50 hours, additional ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (Intermediate 121, 15 g, 69 mmol) and InBr₃ (1 g, 2.8 mmol) were added. After 30 hours, the mixture was poured into water and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate=100:1 to 2:1) to provide the title compound as a yellow oil (900 mg, 12%). MS (ESI): mass calcd. for C₃₀H₄₄F₂N₄O₃Si, 574.3 m/z found, 575.2 [M+H]⁺.

Step D: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. A 1 M solution of TBAF in THF (2.7 mL, 2.7 mmol) was added dropwise to a stirring solution of tert-butyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (900 mg, 1.3 mmol) in THF (15 mL). After 4 hours, the mixture was poured into water and then extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate) to provide the title compound as a yellow oil (450 mg, 71%). MS (ESI): mass calcd. for C₂₄H₃₀F₂N₄O₃, 460.2 m/z found, 461.1 [M+H]⁺.

Intermediate 192 tert-Butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate

SOCl₂ (0.4 mL, 6 mmol) was added to a stirring solution of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (Intermediate 191, 450 mg, 0.98 mmol) in dichloromethane (8 mL). After 1 hour, the mixture was concentrated to dryness under reduced pressure. The residue was used without further purification. MS (ESI): mass calcd. for C₂₄H₂₉ClF₂N₄O₃, 478.2 m/z found, 479.1 [M+H]⁺.

Intermediate 193 tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate

The title compound (350 mg) was prepared using analogous conditions as described in Intermediate 191 where 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (Intermediate 57) was used instead of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde in Step A. MS (ESI): mass calcd. for C₂₄H₃₀F₂N₄O₃, 460.2 m/z found, 461.2 [M+H]⁺.

Intermediate 194 tert-Butyl 3-(6-(chloromethyl)-5-m ethylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate

The title compound (320 mg) was prepared using analogous conditions as described in Intermediate 192 where tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (Intermediate 193) was used instead of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. MS (ESI): mass calcd. for C₂₄H₂₉ClF₂N₄O₃, 478.2 m/z found, 479.2 [M+H]⁺.

Intermediate 195 Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate

The title compound (330 mg) was prepared using analogous conditions as described in Intermediate 191 where 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (Intermediate 57) was used instead of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde in Step A and where ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane was used instead of ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane in Step C. MS (ESI): mass calcd. for C₂₁H₂₄F₂N₄O₃, 418.2 m/z found, 419.2 [M+H]⁺.

Intermediate 196 Methyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate

The title compound (350 mg) was prepared using analogous conditions as described in Intermediate 192 where methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (Intermediate 195) was used instead of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. MS (ESI): mass calcd. for C₂₁H₂₃ClF₂N₄O₂, 436.2 m/z found, 437.2 [M+H]⁺.

Intermediate 197: tert-Butyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: (6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. The title compound was prepared using analogous conditions as described in Intermediate 191: Step A where 7-iodo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 53) was used instead of 3-(difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. MS (ESI): mass calcd. for C₂₂H₂₉F₃N₄O₂Si, 466.2 m/z found, 467.2 [M+H]⁺.

Step B: tert-Butyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound was prepared using analogous conditions as described in Example 17: Step B where (6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol was used instead of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol and ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (Intermediate 121) was used instead of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane and dichloroethane was used instead of acetonitrile as solvent. MS (ESI): mass calcd. for C₃₀H₄₃F₃N₄O₃Si, 592.3 m/z found, 593.1 [M+H]⁺.

Step C: tert-Butyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound was prepared using analogous conditions as described in Intermediate 191: Step D where tert-butyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of tert-butyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. MS (ESI): mass calcd. for C₂₄H₂₉F₃N₄O₃, 478.2 m/z found, 479.1 [M+H]⁺.

Intermediate 198: tert-Butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The title compound (700 mg) was prepared using analogous conditions as described in Intermediate 192 where tert-butyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 197) was used instead of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. MS (ESI): mass calcd. for C₂₄H₂₈ClF₃N₄O₂, 496.2 m/z found, 497.2 [M+H]⁺.

Intermediate 199: Benzyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

Step A: 3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoic acid. LiOH.H₂O (1.6 g, 38 mmol) was added to a solution of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (Intermediate 55, Step E, 4.0 g, 7.7 mmol) and 1,4-dioxane: H₂O (1:1, 60 mL). The resulting mixture was stirred at 75° C. for 16 hours, then was cooled to room temperature and adjusted to pH=6 using 1N HCl. The organic solvent was removed under reduced pressure and the mixture extracted with ethyl acetate (50 mL×5). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to provide the title compound (2.2 g, 67%) as yellow solid. MS (ESI): mass calcd. for C₂₃H₂₇N₃O₃ 393.48; m/z found, 394.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=6.6 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.04 (br s, 2H), 5.03 (br s, 1H), 5.15-4.88 (m, 1H), 4.71 (s, 1H), 4.41 (s, 2H), 2.53 (s, 2H), 2.32 (s, 1H), 2.16 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 1.11-0.89 (m, 4H).

Step B: Benzyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. Benzyl bromide (0.16 mL, 1.3 mmol) was added to a mixture of 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoic acid (500 mg, 1.27 mmol), K₂CO₃ (439 mg, 3.18 mmol), and MeCN (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The suspension was filtered, and the filter cake was washed with ethyl acetate (4 mL×3). The filtrate was concentrated to dryness under reduced pressure and purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 0:1) to provide the title compound (330 mg, 53%) as a yellow oil. MS (ESI): mass calcd. for C₃₀H₃₃N₃O₃ 483.60; m/z found, 484.7 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J=7.3 Hz, 1H), 7.21-7.11 (m, 4H), 7.08-6.99 (m, 4H), 6.89 (d, J=7.3 Hz, 1H), 5.07-5.01 (m, 1H), 4.97-4.90 (m, 1H), 4.73 (s, 1H), 4.59 (s, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 1.98-1.91 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H), 1.27-1.07 (m, 4H).

Step C: Benzyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. Benzyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (2.2 g, 4.5 mmol) was purified by chiral SFC (DAICEL CHIRALPAK AD, mobile phase: 60% CO₂, 40% EtOH containing 0.1% of 25% aq. NH₃ to afford two enantiomers. The first eluting isomer (980 mg, 45%) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₃N₃O₃ 483.60; m/z found, 484.3 [M+H]⁺.

Intermediate 200: Benzyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

The second eluting isomer (1.0 g, 44%) from the chiral separation described in Intermediate 199 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₃N₃O₃ 483.60; m/z found, 484.3 [M+H]⁺.

Intermediate 201: 7′-Bromo-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

The title compound (8.2 g) was prepared using analogous conditions as described in Intermediate 72, Steps A and B using 1-(aminomethyl)cyclopropan-1-ol instead of 4-(aminomethyl)tetrahydro-2H-pyran-4-ol in Step A. MS (ESI): mass calcd. for C₁₀H₁₁BrN₂O₃S 318.0 m/z found 319.0 [M+H]⁺.

Intermediate 202: 7′-(2-(4-Fluoropiperidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide

Step A: 2-(4-Fluoropiperidin-1-yl)ethanol. 2-Bromoethanol (5.10 mL, 72.0 mmol) was added to a solution of 4-fluoropiperidine hydrochloride (5.0 g, 35.8 mmol), K₂CO₃ (34.7 g, 251 mmol), and CH₃CN (70 mL). The resulting mixture was stirred at 90° C. for 16 hours before concentrating to dryness under reduced pressure. H₂O (20 mL) was added to the residue and the mixture extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure afford the title compound (4.5 g), which was used in the next step without further purification. MS (ESI): mass calcd. for C₇H₁₄FNO 147.1 m/z found 148.0 [M+H]⁺.

Step B: 7′-((2-(4-Fluoropiperidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. 2-(4-Fluoropiperidin-1-yl)ethanol (922 mg, 6.25 mol) and Cs₂CO₃ (2.45 g, 7.52 mmol) were added to a solution of 7′-bromo-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 201, 800 mg, 2.51 mmol) and DMA (10 mL). The mixture was sparged with Na for 5 minutes and then treated with JosiPhos pre-catalyst G3 (116 mg, 0.126 mmol). The resulting mixture was sparged with Na for an additional 5 minutes and then stirred while heating at 100° C. for 18 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 0:1, gradient) to afford the title compound (650 mg, 67%). MS (ESI): mass calcd. for C₁₇H₂₄FN₃O₄S 385.2 m/z; 386.2 found [M+H]⁺.

Intermediate 203: Benzyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

Step A: 3-(3-(Hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (35.1 g) was prepared using analogous conditions as described in Example 330, Step F using methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 17, Step B) instead of methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃ 421.2; m/z found, 422.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (br s, 1H), 8.42 (d, J=7.1 Hz, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.14 (dd, J=1.7, 7.8 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 5.07-5.00 (m, 1H), 4.78 (s, 1H), 4.41 (d, J=4.6 Hz, 2H), 2.66 (s, 3H), 2.16 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H).

Step B: Benzyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Benzyl bromide (9.9 mL, 83 mmol) was added to a stirring mixture containing 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (35.1 g, 75.7 mmol), K₂CO₃ (26.3 g, 190 mmol) in CH₃CN (400 mL) at room temperature. After 16 hours, the mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was combined with an additional batch and concentrated to dryness under reduced pressure. The filtrate was purified by column chromatography (petroleum ether: ethyl acetate=1:0 to 1:1) to afford the title compound (37.2 g) as a yellow oil. MS (ESI): mass calcd. for C₂₄H₂₈F₃N₃O₃ 511.2; m/z found, 512.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (d, J=7.3 Hz, 1H), 7.22 (d, J=6.8 Hz, 2H), 7.07-6.97 (m, 7H), 5.06-4.97 (m, 2H), 4.84 (d, J=12.1 Hz, 1H), 4.67 (s, 1H), 4.37 (d, J=5.3 Hz, 2H), 2.50 (s, 3H), 2.13 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H).

Step C: Benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and Benzyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The mixture of benzyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate enantiomers were separated by chiral SFC (stationary phase: REGIS (s,s) WHELK-O1 250 mm×50 mm, 10 μm; eluent: 35% to 35% (v/v) supercritical CO₂ in ethanol and H₂O with 0.1% NH₃). The first eluting isomer (12.4 g) was designated (*S): MS (ESI): mass calcd. for C₂₄H₂₈F₃N₃O₃ 511.2; m/z found, 512.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=7.3 Hz, 1H), 7.27-7.21 (m, 2H), 7.09-7.01 (m, 7H), 5.09-5.00 (m, 2H), 4.87 (d, J=12.3 Hz, 1H), 4.70 (s, 1H), 4.40 (d, J=5.5 Hz, 2H), 2.53 (s, 3H), 2.16 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H) and the second eluting isomer (12.5 g) was designated (*R): MS (ESI): mass calcd. for C₂₈H₂₈F₃N₃O₃ 511.2; m/z found, 512.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=7.3 Hz, 1H), 7.27-7.23 (m, 2H), 7.10-7.00 (m, 7H), 5.09-5.00 (m, 2H), 4.87 (d, J=12.1 Hz, 1H), 4.71 (s, 1H), 4.40 (d, J=5.3 Hz, 2H), 2.53 (s, 3H), 2.16 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H).

Step D: Benzyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (1.0 g) was prepared using analogous conditions as described in Example 17, Step C using benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate instead of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₂₄H₂₇ClF₃N₃O₂ 529.2; m/z found, 530.2 [M+H]⁺.

Intermediate 204: Benzyl (*R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate

The title compound (1.0 g) was prepared using analogous conditions as described in Example 17, Step C using benzyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 203, Step C: second eluting isomer) instead of methyl 3-(3-4(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₂₈H₂₇ClF₃N₃O₂ 529.2; m/z found, 530.2 [M+H]⁺.

Example 1: 3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetic acid salt

Step A: Methyl (E)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. To a solution of 5-bromo-7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 33, 6.71 g, 24.1 mmol) in DMF (6.5 mL) was added sequentially methyl acrylate (10.9 mL, 121 mmol), DIPEA (10.4 mL, 60.3 mmol), tri-o-tolylphosphine (1.47 g, 4.83 mmol), and Pd(OAc)₂ (542 mg, 2.41 mmol). The reaction vessel was evacuated and back-filled with Ar and was heated to 100° C. for 24 hours. The reaction mixture was then allowed to cool to room temperature and was stirred for 2 days. The reaction mixture was filtered through a pad of diatomaceous earth such as Celite®, and the pad was washed with EtOAc. The organic filtrate was washed with water (twice) and saturated aqueous NaCl (once). The organic phase was dried (Na₂SO₄), filtered, and concentrated onto silica gel. Flash column chromatography (eluent: 0 to 40% EtOAc/heptanes, gradient elution) provided the title compound (3.29 g) as brown solid which still contained some impurities. MS (ESI): mass calcd. for C₁₂H₁₁F₂N₃O₃, 283.1; m/z found, 284.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.78 (d, J=15.7 Hz, 1H), 7.34 (s, 1H), 6.75 (t, J=72.0 Hz, 1H), 6.47 (d, J=16.2 Hz, 1H), 4.46 (s, 3H), 3.84 (s, 3H).

Step B: Methyl 3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. To a solution of methyl (E)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (327 mg, 1.16 mmol) in a mixture of 1,4-dioxane (8 mL) and water (deionized, 4 mL) was added sequentially 3-(hydroxymethyl)-4-methylphenyl)boronic acid (288 mg, 1.73 mmol), Et₃N (0.241 mL, 1.73 mmol) and chloro(1,5-cyclooctadiene)rhodium(I) dimer (28.5 mg, 0.0578 mmol). The reaction vessel was evacuated and back-filled with Ar. The mixture was heated to 95° C. for 50 minutes.

The reaction mixture was partitioned between EtOAc and water (25 mL each). The aqueous phase was extracted with EtOAc (2×25 mL). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0 to 100% EtOAc/heptanes, gradient elution) to provide the title compound (334 mg, 71%) as a light tan foam. MS (ESI): mass calcd. for C₂₀H₂₁F₂N₃O₄, 405.2; m/z found, 406.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.23 (s, 1H), 7.14-7.09 (m, 1H), 7.09-7.05 (m, 1H), 7.00 (s, 1H), 6.64 (t, J=72.8 Hz, 1H), 4.70-4.64 (m, 3H), 4.41 (s, 3H), 3.60 (s, 3H), 3.18-3.04 (m, 2H), 2.30 (s, 3H).

Step C: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. To a solution of methyl 3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (272 mg, 0.671 mmol) in DCM (3 mL) was added SOCl₂ (0.073 mL, 1.01 mmol) followed by 2 drops of DMF. The reaction mixture was stirred under Ar at room temperature for 2.5 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO₃. The aqueous phase was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (260 mg, 91%) as a light brown oil. MS (ESI): mass calcd. for C₂₀H₂₀ClF₂N₃O₃, 423.1; m/z found, 424.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.19-7.07 (m, 3H), 6.98 (s, 1H), 6.63 (t, J=72.5 Hz, 1H), 4.66 (t, J=7.8 Hz, 1H), 4.55 (s, 2H), 4.41 (s, 3H), 3.61 (s, 3H), 3.18-3.03 (m, 2H), 2.38 (s, 3H).

Step D: 3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. (*R)-7,7a,8,9,10,11-Hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3, 83.6 mg, 0.330 mmol) was dissolved in DMF (0.75 mL). The solution was cooled to 0° C. and NaH (60% dispersion in mineral oil, 39.6 mg, 0.990 mmol) was added. The mixture was stirred at 0° C. for 10 minutes and a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate in DMF (0.30 M, 1.0 mL, 0.30 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was filtered, washing with a minimal volume of MeOH. The filtrate was purified by preparative HPLC (10 to 90% CH₃CN/H₂O, 0.1% TFA) to afford the title compound (54 mg, 23%) as a cream-colored powder and its trifluoroacetic acid salt. MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S, 626.2; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.26 (m, 2H), 7.71-7.62 (m, 1H), 7.19-6.90 (m, 5H), 6.88-6.45 (m, 1H), 4.71-4.51 (m, 2H), 4.45-4.29 (m, 5H), 4.06-3.80 (m, 1H), 3.47-3.24 (m, 2H), 3.17-2.62 (m, 2H), 2.35-2.25 (m, 3H), 1.83-1.23 (m, 7H).

Example 2: (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 1, 45.6 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm, 250×20 mm, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereoisomers. The first eluting isomer (19 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S, 626.2; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.25 (dd, J=4.8, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.8 Hz, 1H), 7.77 (s, 1H), 7.33-7.03 (m, 5H), 6.92-6.82 (m, 1H), 4.73-4.57 (m, 1H), 4.41 (s, 3H), 4.38-4.21 (m, 3H), 4.06 (td, J=13.5, 4.6 Hz, 1H), 3.28-2.94 (m, 5H), 2.20 (s, 3H), 1.66-1.25 (m, 6H).

Example 3: (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (20 mg) from the separation of isomers by chiral SFC described in Example 2 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S, 626.2; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.25 (dd, J=4.6, 1.5 Hz, 1H), 8.00 (dd, J=7.8, 1.8 Hz, 1H), 7.75 (br s, 1H), 7.32-7.03 (m, 5H), 6.93-6.82 (m, 1H), 4.66 (br s, 1H), 4.41 (s, 3H), 4.39-4.19 (m, 3H), 4.04 (td, J=13.3, 4.7 Hz, 1H), 3.28-2.98 (m, 5H), 2.21 (s, 3H), 1.72-1.27 (m, 6H).

Example 4: 3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetic acid salt

Step A: Methyl (L)-3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate. A mixture containing 5-bromo-7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazole (Intermediate 34, 1.21 g, 4.51 mmol), tetrabutylammonium chloride hydrate (0.134 g, 0.451 mmol), N,N-dicyclohexylmethylamine (1.4 mL, 6.6 mmol), methyl acrylate (0.81 mL, 9.0 mmol), PdCl₂(dtbpf) (0.296 g, 0.455 mmol), and DMA (7.5 mL) was heated to 120° C. under argon in a sealed tube. After 3 hours, the reaction was diluted with water (75 mL) and extracted with 1:1 diethyl ether: EtOAc (2×40 mL). These extractions resulted in multiple organic solvent fractions which were combined, washed sequentially with 0.1 M HCl (1×40 mL), 1 M NaHCO₃(1×20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: heptanes/ethyl acetate, 90:10 to 20:80, gradient elution) to provide the title compound (1.04 g, 84%). MS (ESI): mass calcd. for C₁₄H₁₅N₃O₃, 273.1; m/z found, 274.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=15.7 Hz, 1H), 7.74 (s, 1H), 7.30 (d, J=1.0 Hz, 1H), 6.47 (d, J=15.7 Hz, 1H), 4.41 (s, 3H), 3.97-3.91 (m, 1H), 3.84 (s, 3H), 0.99-0.87 (m, 4H).

Step B: Methyl 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. A solution of methyl (E)-3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (180.9 mg, 0.6619 mmol), 3-hydroxymethyl-4-methylphenylboronic acid (163.8 mg, 0.9868 mmol) and TEA (0.28 mL, 2.0 mmol) in 1,4-dioxane (2.6 mL) and water (1.3 mL, 0.65 mmol) was charged with [Rh(COD)Cl]₂ (33 mg, 0.067 mmol) and stirred under argon at 60° C. for 60 hours. The reaction was partitioned between EtOAc (6 mL) and 1 M NaH₂PO₄ (6 mL). The organic and aqueous layers were separated and the aqueous layer was extracted with EtOAc (1×3 mL). These extractions resulted in multiple organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: heptanes/ethyl acetate, 60:40 to 0:100, gradient elution) to provide the title compound (168 mg, 64%). MS (ESI): mass calcd. for C₂₂H₂₅N₃O₄, 395.2; m/z found, 396.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (br s, 1H), 7.28-7.27 (m, 1H), 7.11 (s, 2H), 7.01-6.97 (m, 1H), 4.70-4.63 (m, 3H), 4.35 (s, 3H), 3.86-3.80 (m, 1H), 3.86-3.80 (m, 1H), 3.61 (s, 3H), 3.12 (br s, 2H), 2.30 (s, 3H), 0.93-0.77 (m, 4H).

Step C: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. A solution containing methyl 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (162.5 mg, 0.411 mmol) in DCM (1.7 mL) was treated with thionyl chloride (0.12 mL, 1.7 mmol) dropwise at room temperature over 10 seconds followed by dropwise addition of DMF (22 μL, 0.28 mmol). After 35 minutes, the reaction was diluted with DCM (4 mL) and cooled to 0° C. while 1 M aqueous NaHCO₃ solution (6 mL) was added in one portion. After 5 minutes at 0° C., the mixture was warmed room temperature for 10 minutes and the aqueous layer was extracted with DCM (1×4 mL). These extractions resulted in multiple organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness to provide the title compound (183 mg) which was carried on to the next step without further purification. MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₃, 413.2; m/z found, 414.1 [M+H]⁺.

Step D: Methyl 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate. A solution containing (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 54.7 mg, 0.229 mmol) and DMF (0.52 mL) was treated with NaH (60.8% dispersion in mineral oil, 13.2 mg, 0.334 mmol) in one portion at room temperature, and was then immediately cooled to 0° C. and stirred under argon for 10 minutes. The reaction was then treated dropwise with a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (91 mg, 0.22 mmol) in DMF (0.56 mL) over 2 minutes, and stirred at 0° C. for 20 minutes. The reaction was then quenched with 1 M NaH₂PO₄ (3 mL) and extracted with EtOAc (2×3 mL). These extractions resulted in multiple organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (141 mg) which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.3; m/z found, 617.3 [M+H]⁺.

Step E: 3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing methyl[f]pyrrolo[2,1-d]-[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (127 mg, 0.206 mmol), 1.0 M LiOH (0.68 mL, 0.68 mmol), MeOH (0.91 mL) and THF (0.91 mL) was stirred at 60° C. for 40 minutes. The reaction mixture was then allowed to cool to room temperature and the pH adjusted to pH-2 with TFA (0.068 mL), diluted with MeOH (3 mL), and purified by C₁₈ reverse phase HPLC (30×100 mm Phenomenex Luna 5 μm column; 10 to 90% CH₃CN with 0.1% TFA) to provide, after lyophilization, the title compound and its trifluoroacetic acid salt. (85.2 mg, 58%). MS (ESI): mass calcd. for C₃₁H₃₄N₆O₅S, 602.2; m/z found, 603.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25-8.19 (m, 2H), 7.39 (d, J=12.1 Hz, 1H), 7.25 (td, J=7.7, 2.5 Hz, 1H), 7.20-7.12 (m, 3H), 6.95 (ddd, J=7.7, 5.2, 1.3 Hz, 1H), 4.69-4.59 (m, 2H), 4.44 (dd, J=14.1, 4.5 Hz, 1H), 4.36 (s, 3H), 4.20 (dd, J=14.4, 7.3 Hz, 1H), 3.98-3.93 (m, 1H), 3.64-3.51 (m, 2H), 3.24 (ddd, J=16.9, 13.4, 3.5 Hz, 1H), 3.17-3.06 (m, 2H), 3.02-2.90 (m, 1H), 2.27-2.26 (s, 3H), 2.06-1.92 (m, 1H), 1.86-1.61 (m, 2H), 1.53-1.44 (m, 1H), 0.90-0.75 (m, 4H).

Example 5: (*S)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 4) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 70% CO₂, 30% EtOH) to afford two diastereomers. The first eluting isomer (30 mg, 44%) was designated (*S). MS (ESI): mass calcd. for C₃₁H₃₄N₆O₅S, 602.2; m/z found, 602.2 [M]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.26 (dd, J=4.8, 1.8 Hz, 1H), 8.04 (dd, J=7.6, 2.0 Hz, 1H), 7.41 (s, 1H), 7.25 (dd, J=7.6, 2.0 Hz, 1H), 7.18-7.13 (m, 3H), 6.86 (dd, J=7.8, 4.8 Hz, 1H), 4.62 (t, J=7.8 Hz, 1H), 4.46 (br s, 1H), 4.42-4.38 (m, 1H), 4.36 (s, 3H), 4.19 (d, J=14.1 Hz, 1H), 3.95 (tt, J=5.9, 2.9 Hz, 1H), 3.60 (dt, J=10.9, 6.1 Hz, 1H), 3.52-3.40 (m, 1H), 3.20 (dd, J=13.6, 3.5 Hz, 1H), 3.16-3.04 (m, 2H), 2.96-2.86 (m, 1H), 2.26 (s, 3H), 2.02-1.89 (m, 1H), 1.75-1.51 (m, 2H), 1.48-1.39 (m, 1H), 0.93-0.75 (m, 4H).

Example 6: (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (26.1 mg, 39%) from the separation of isomers by chiral SFC described in Example 5 was designated (*R). MS (ESI): mass calcd. for C₃₁H₃₄N₆O₅S, 602.2; m/z found, 602.2 [M]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (dd, J=5.1, 1.5 Hz, 1H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 7.39 (s, 1H), 7.26-7.21 (m, 1H), 7.20-7.12 (m, 3H), 6.89 (dd, J=7.6, 5.1 Hz, 1H), 4.63 (t, J=7.8 Hz, 1H), 4.48 (br s, 1H), 4.40 (s, 1H), 4.36 (s, 3H), 4.22 (d, J=14.1 Hz, 1H), 3.96 (tt, J=6.0, 2.8 Hz, 1H), 3.67-3.57 (m, 1H), 3.57-3.47 (m, 1H), 3.18 (dd, J=13.6, 3.5 Hz, 1H), 3.15-3.08 (m, 2H), 2.99-2.91 (m, 1H), 2.27 (s, 3H), 1.99-1.88 (m, 1H), 1.81-1.55 (m, 2H), 1.53-1.33 (m, 1H), 0.92-0.75 (m, 4H).

Example 7: (*S)-3-(3 41′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.1 mL, 0.5 mmol) was added to a mixture of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 25, 130 mg, 0.31 mmol), 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 5, 97.7 mg, 0.432 mmol), and triphenyl phosphine (120 mg, 0.46 mmol) in THF (3.5 mL) at room temperature. After 3 hours, ethyl acetate was added and then the mixture was absorbed onto diatomaceous earth such as Celite® for purification by flash column chromatography (hexanes/ethyl acetate) to provide the title compound (205 mg, 106%). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.2 [M+H]⁺.

Step B: (*S)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture of ethyl 3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (205 mg, 0.326 mmol) in 1 M aqueous NaOH solution (3 mL, 3 mmol) and THF (3 mL) was stirred at room temperature. After 18 hours, water was added and then 1 M aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 300 gram, isocratic mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting isomer (55 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₅S, 601.2; m/z found, 602.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.3 (br s, 1H), 8.54-8.47 (m, 1H), 8.39 (d, J=7.2 Hz, 1H), 8.26 (dd, J=7.7, 1.9 Hz, 1H), 7.50 (dd, J=7.6, 4.9 Hz, 1H), 7.26-7.20 (m, 1H), 7.19-7.11 (m, 3H), 4.81 (t, J=7.8 Hz, 1H), 4.28-4.13 (m, 2H), 3.69-3.54 (m, 1H), 3.50-3.39 (m, 1H), 3.14-2.99 (m, 2H), 2.71 (s, 3H), 2.22 (s, 3H), 1.01-0.87 (m, 2H), 0.69-0.55 (m, 2H).

Example 8: (*R)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (53 mg) from the separation of isomers by chiral SFC described in Example 7 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₅S, 601.2; m/z found, 602.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (dd, J=4.9, 1.9 Hz, 1H), 8.39 (d, J=7.1 Hz, 1H), 8.26 (dd, J=7.6, 1.9 Hz, 1H), 7.53-7.47 (m, 1H), 7.25-7.20 (m, 1H), 7.18-7.11 (m, 3H), 4.86-4.75 (m, 1H), 4.29-4.12 (m, 2H), 3.70-3.53 (m, 1H), 3.53-3.38 (m, 1H), 3.13-3.00 (m, 2H), 2.71 (s, 3H), 2.22 (s, 3H), 1.00-0.85 (m, 2H), 0.69-0.54 (m, 2H).

Example 9: (*S)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*3S)-3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Di-tert-butyl azodicarboxylate (601 mg, 2.61 mmol) was added to a solution of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 693 mg, 1.64 mmol), 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 9, 561 mg, 2.02 mmol), and triphenyl phosphine (691 mg, 2.63 mmol) in THF (24 mL) at room temperature. After 30 minutes, additional triphenyl phosphine (201 mg) and di-tert-butyl azodicarboxylate (170 mg) were added and the mixture was stirred overnight. The mixture was absorbed onto diatomaceous earth such as Celite® for purification by flash column chromatography (hexanes/ethyl acetate) to provide the title compound which still contained impurities. The residue was further purified by reverse phase-flash column chromatography (C₁₈ column, acetonitrile-water containing 0.05% TFA). The pure fractions resulting from the reverse phase-flash column chromatography were collected, concentrated under reduced pressure, and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound as a white solid (1.01 g, 90%). MS (ESI): mass calcd. for C₃₃H₃₄F₃N₇O₄S, 681.2; m/z found, 682.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69-8.65 (m, 1H), 8.45-8.40 (m, 2H), 7.33-7.13 (m, 4H), 4.93-4.77 (m, 1H), 4.51-4.09 (m, 4H), 4.03-3.93 (m, 2H), 3.35-3.09 (m, 5H), 2.79-2.70 (m, 3H), 2.16-2.10 (m, 3H), 1.69-1.25 (m, 6H), 1.12-1.01 (m, 3H).

Step B: (*S)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl (*3S)-3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.01 g, 1.48 mmol), 1 M aqueous NaOH solution (4.4 mL, 4.4 mmol) and THF (8 mL) was stirred at room temperature. After 2 hours, additional 1 M aqueous NaOH solution (4.4 mL) and THF (4 mL) were added. After 6 hours, water was added and then 1 M aqueous HCl solution until the pH was 3-4. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and then absorbed onto diatomaceous earth such as Celite® for purification by reverse phase-flash column chromatography (C₁₈ column, acetonitrile-water containing 0.05% TFA). The pure fractions resulting from the reverse phase-flash column chromatography were collected, concentrated under reduced pressure, and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford a mixture of isomers (934 mg, 96%). The isomeric mixture was separated by chiral SFC (stationary phase: Daicel Chiralpak IG, 2×25 cm, mobile phase: 60% CO₂, 40% MeOH) to provide two diastereoisomers. The first eluting isomer (441 mg) was designated (*R). MS (ESI): mass calcd. for C₃₁H₃₀F₃N₇O₄S, 653.2; m/z found, 654.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.37 (s, 1H), 8.67 (d, J=2.1 Hz, 1H), 8.48-8.37 (m, 2H), 7.33-7.10 (m, 4H), 4.87-4.76 (m, 1H), 4.46-4.36 (m, 1H), 4.36-4.20 (m, 2H), 4.20-4.09 (m, 1H), 3.38-3.03 (m, 5H), 2.73 (s, 3H), 2.12 (s, 3H), 1.65-1.21 (m, 6H).

Example 10: (*S)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (449 mg) from the separation of isomers by chiral SFC described in Example 9 was designated (*S). MS (ESI): mass calcd. for C₃₁H₃₀F₃N₇O₄S, 653.2; m/z found, 654.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.48-8.33 (m, 2H), 7.36-7.08 (m, 4H), 4.90-4.79 (m, 1H), 4.51-4.33 (m, 2H), 4.21-4.09 (m, 2H), 3.41-3.04 (m, 5H), 2.76 (s, 3H), 2.14 (s, 3H), 1.67-1.14 (m, 6H).

Example 11: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

Step A: Ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate. To a 100 mL round bottom flask under N₂ was added ethyl (E)-3-1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acrylate (Intermediate 35, 1.00 g, 3.51 mmol), (3-(hydroxymethyl)-4-methylphenyl)boronic acid (934 mg, 5.63 mmol) and TEA (1.30 mL, 9.35 mmol) in 1,4-dioxane (17.0 mL) and water (7.00 mL). [Rh(COD)Cl]₂ (254 mg, 0.52 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was poured into aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3×). These extractions resulted in several organic solvent fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/DCM, 1:1) to afford the title compound (1.15 g, 81%) as a colorless oil. MS (ESI): mass calcd. for C₂₄H₂₉N₃O₃, 407.2; m/z found, 408.2 [M+H]⁺.

Step B: Ethyl 3-(1-(cyclopropylmethyl)-4-methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoate. To a reaction vessel under N₂ was added ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (200 mg, 0.49 mmol), (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39, 174 mg, 0.69 mmol), triphenyl phosphine (244 mg, 0.93 mmol) and THF (6.00 mL). Diisopropyl azodicarboxylate (0.18 mL, 0.91 mmol) was then added to this mixture, and the reaction was allowed to stir at room temperature for 18 hours. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution and the aqueous layer was extracted with ethyl acetate (2×). These extractions resulted in several organic solvent fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/DCM, 1:1) to afford the title compound (260 mg, 82%) as a colorless, solid. MS (ESI): mass calcd. for C₃₅H₄₂N₆O₄S, 642.3; m/z found, 642.9 [M+H]⁺.

Step C: 3-(1-(Cyclopropylmethyl)-4-methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid. To a reaction vessel containing ethyl 3-(1-(cyclopropylmethyl)-4-methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoate (260 mg, 0.40 mmol) was added 1 M NaOH (3.70 mL), THF (3.70 mL) and ethanol (0.40 mL). This mixture was stirred for 18 hours at room temperature followed by adjustment of the pH to pH 3-5 with 2 M HCl. The mixture was partitioned between water and ethyl acetate, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×). These extractions resulted in several organic solvent fractions which were combined, washed with brine (1×), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (245 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.37-8.35 (m, 1H), 8.16-8.12 (m, 1H), 7.38-7.34 (m, 2H), 7.16 (d, J=13.8 Hz, 1H), 7.12-7.04 (m, 2H), 6.92-6.89 (m, 1H), 4.99-4.95 (m, 1H), 4.73 (dd, J=14.9, 5.8 Hz, 1H), 4.45 (dd, J=7.1, 4.0 Hz, 2H), 4.27 (dd, J=14.9, 3.2 Hz, 1H), 3.93-3.85 (m, 1H), 3.60-3.44 (m, 2H), 3.24-3.03 (m, 2H), 2.89-2.70 (m, 4H), 2.26 (d, J=5.7 Hz, 3H), 1.88-1.59 (m, 4H), 1.42-1.14 (m, 3H), 0.76-0.70 (m, 2H), 0.66-0.57 (m, 2H), 0.49-0.44 (m, 2H).

Example 12: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-34(*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid isomers (Example 11, 245 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, mobile phase: 50% CO₂, 50% MeOH) to afford two diastereoisomers. The first eluting isomer (99 mg) was designated (*S). MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (dd, J=4.8, 1.8 Hz, 1H), 8.14 (dd, J=7.7, 1.9 Hz, 1H), 7.37 (d, J=1.4 Hz, 2H), 7.15 (s, 1H), 7.08 (s, 2H), 6.91 (dd, J=7.7, 4.8 Hz, 1H), 4.97 (t, J=7.7 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.45 (d, J=7.0 Hz, 2H), 4.27 (d, J=14.8 Hz, 1H), 3.90-3.83 (m, 1H), 3.75-3.70 (m, 0.5H), 3.58-3.44 (m, 1.5H), 3.21-3.11 (m, 2H), 2.86-2.70 (m, 4H), 2.27 (s, 3H), 1.81-1.54 (m, 4H), 1.42-1.15 (m, 2H), 0.75 (s, 3H), 0.66-0.56 (m, 2H), 0.47-0.43 (m, 2H).

Example 13: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (100 mg) from the separation of isomers by chiral SFC described in Example 12 was designated (*R). MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (dd, J=4.8, 1.8 Hz, 1H), 8.14 (dd, J=7.7, 1.9 Hz, 1H), 7.36-7.32 (m, 2H), 7.15 (s, 1H), 7.08-7.07 (m, 2H), 6.91 (dd, J=7.7, 4.8 Hz, 1H), 4.97 (t, J=7.7 Hz, 1H), 4.73 (d, J=14.8 Hz, 1H), 4.45 (d, J=7.0 Hz, 2H), 4.27 (d, J=14.8 Hz, 1H), 3.93-3.98 (m, 1H), 3.58-3.44 (m, 2H), 3.20-3.17 (m, 1H), 3.11-3.07 (m, 1H), 2.86-2.70 (m, 4H), 2.27 (s, 3H), 1.85-1.73 (m, 4H), 1.42-1.15 (m, 2H), 0.69 (s, 3H), 0.66-0.56 (m, 2H), 0.47-0.43 (m, 2H).

Example 14: 3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

Step A: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. A solution of n-BuLi (0.700 mL, 2.5 M in hexanes, 1.75 mmol) was added dropwise to ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 472 mg, 1.58 mmol) in THF at −78° C. (20 mL) and the resulting mixture was stirred for 1 hour. 1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (Intermediate 22, 298 mg, 1.50 mmol) in THF (5 mL) was added dropwise and the resulting solution was warmed to room temperature over a period of 4 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 10% acetone in CH₂Cl₂) to provide the title compound (450 mg, 70%). MS (ESI): mass calcd. for C₂₄H₃₅N₃O₂Si, 425.2; m/z found, 426.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (d, J=8.6 Hz, 1H), 7.40-7.30 (m, 2H), 7.20 (dd, J=7.7, 2.0 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.75 (br s, 1H), 6.23 (s, 1H), 4.69-4.62 (m, 4H), 2.74 (s, 3H), 2.21 (s, 3H), 1.59 (t, J=7.3 Hz, 3H), 0.82 (s, 9H), 0.10 (s, 6H).

Step B: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. 2,2,2-Trichloroacetonitrile (397 mg, 2.75 mmol) and DBU (7.60 mg, 0.0499 mmol) were added to (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (450 mg, 1.08 mmol) in acetonitrile (5 mL) at room temperature, and the mixture was stirred for 45 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (438 mg, 2.51 mmol) and bis(trifluoromethanesulfonyl)imide (32.0 mg, 0.114 mmol) were then added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with aqueous saturated NaHCO₃ solution (20 mL), and extracted with DCM (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was then dissolved in DCM (10 mL) and SOCl₂ (0.31 mL, 4.3 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was purified by flash column chromatography (eluent: 10% acetone in CH₂Cl₂) to provide the title compound (250 mg, 57%). MS (ESI): mass calcd. for C₂₃H₂₈ClN₃O₂, 413.2; m/z found, 414.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d, J=8.7 Hz, 1H), 7.32-7.27 (m, 1H), 7.17-7.09 (m, 2H), 7.08-7.04 (m, 1H), 4.86 (s, 1H), 4.69-4.60 (m, 2H), 4.57-4.50 (m, 2H), 2.72 (s, 3H), 3.50 (s, 3H), 2.34 (s, 3H), 1.66-1.54 (m, 3H), 1.40 (s, 3H), 1.31 (s, 3H).

Step C: 3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid. DMF (0.5 mL) was added to a mixture of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 33 mg, 0.12 mmol) and sodium hydride (60% dispersion in mineral oil, 9.0 mg, 0.24 mmol). After 10 minutes, a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (50 mg, 0.12 mmol) in DMF (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated under reduced pressure. The residue was dissolved in THF (1 mL) and MeOH (1 mL) and then NaOH (3 M, 1 mL, 3 mmol) was added. The mixture was heated to 50° C. for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to ˜3-4 by adding 1 M aqueous HCl solution. This reaction mixture was extracted with ethyl acetate and the organic and aqueous portion separated. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (24 mg, 32%). MS (ESI): mass calcd. for C₃₃H₃₉N₅O₆S, 633.3; m/z found, 633.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.50-8.32 (m, 1H), 8.19-8.09 (m, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.22-7.14 (m, 3H), 6.99 (d, J=7.8 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 5.04 (s, 1H), 4.59-4.50 (m, 2H), 4.47-4.20 (m, 2H), 4.03-3.87 (m, 2H), 3.65-3.56 (m, 1H), 3.49-3.44 (m, 2H), 3.42-3.25 (m, 1H), 2.74 (s, 3H), 2.07 (s, 3H), 1.64-1.33 (m, 7H), 1.20 (s, 3H), 0.95 (s, 3H).

Example 15: (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyri do[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

The mixture of 3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid enantiomers (Example 14, 24 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, mobile phase: 80% CO₂, 20% MeOH) to afford two enantiomers. The first eluting enantiomer (7 mg) was designated (*S). MS (ESI): mass calcd. for C₃₃H₃₉N₅O₆S, 633.3; m/z found, 633.9 [M+H]⁺.

Example 16: (*R)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

The second eluting enantiomer (7 mg) from the separation of isomers by chiral SFC described in Example 15 was designated (*R). MS (ESI): mass calcd. for C₃₃H₃₉N₅O₆S, 633.3; m/z found, 633.9 [M+H]⁺.

Example 17: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. A solution of n-BuLi (2.95 mL, 2.5 M in hexanes, 7.38 mmol) was added dropwise to ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 1.78 g, 5.67 mmol) in THF (80 mL) at −78° C. and the resulting mixture was stirred for 1 hour. 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (Intermediate 22, 1.30 g, 5.67 mmol) in THF (5 mL) was then added dropwise and the resulting solution was warmed to room temperature over a period of 4 hours. Aqueous saturated NH₄Cl solution (40 mL) was added and the aqueous layer was extracted with EtOAc (60 mL×2). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to provide the title compound (1.60 g, 61%). MS (ESI): mass calcd. for C₂₃H₃₀F₃N₃O₂Si, 465.2; m/z found, 466.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=7.2 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.36-7.31 (m, 1H), 7.18 (dd, J=7.7, 2.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.13 (d, J=3.2 Hz, 1H), 4.61 (s, 2H), 2.65-2.61 (m, 4H), 2.18 (s, 3H), 0.82 (s, 9H), 0.01 (d, J=8.5 Hz, 6H).

Step B: Methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 2,2,2-Trichloroacetonitrile (1.29 g, 8.94 mmol) and DBU (80.0 mg, 0.525 mmol) were added to (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (1.60 g, 3.44 mmol) in acetonitrile (5 mL) at room temperature and the mixture was stirred for 45 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.38 g, 7.90 mmol) and bis(trifluoromethanesulfonyl)imide (96.6 mg, 0.344 mmol) were then added sequentially, and the mixture was stirred at room temperature for 16 hours. Another portion of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.38 g, 7.90 mmol) and bis(trifluoromethanesulfonyl)imide (96.6 mg, 0.344 mmol) were then added sequentially, and the mixture was stirred at 50° C. for 16 hours. The reaction was quenched with aqueous saturated NaHCO₃ solution (20 mL), and extracted with EtOAc (50 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc/hexanes) to provide the title compound (1.20 g, 64%). MS (ESI): mass calcd. for C₂₈H₃₈F₃N₃O₃Si, 549.3; m/z found, 550.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J=7.3 Hz, 1H), 7.27-7.14 (m, 2H), 7.01 (d, J=1.3 Hz, 2H), 4.79 (s, 1H), 4.60 (s, 2H), 3.55 (s, 3H), 2.73 (d, J=0.8 Hz, 3H), 2.16 (s, 3H), 1.36 (d, J=32.8 Hz, 6H), 0.83 (s, 9H), 0.00 (d, J=3.6 Hz, 6H).

Step C: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (550 mg, 1.00 mmol) was dissolved in DCM (10 mL), and SOCl₂ (0.31 mL, 4.33 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by flash column chromatography (10% EtOAc/hexanes) to provide the title compound (400 mg, 88%). MS (ESI): mass calcd. for C₂₂H₂₃ClF₃N₃O₂, 453.1; m/z found, 453.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d, J=7.3 Hz, 1H), 7.20-7.02 (m, 4H), 4.79 (s, 1H), 4.62-4.47 (m, 2H), 3.55 (s, 3H), 2.79 (s, 3H), 2.39 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H).

Step D: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. DMF (0.5 mL) was added to a mixture of 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 200 mg, 0.703 mmol) and KO^(t)Bu (118 mg, 1.05 mmol). After 10 minutes, a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (319 mg, 0.703 mmol) in DMF (0.5 mL) was added and the mixture was stirred at room temperature for 1 hour.

Water (20 mL) was added and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated under reduced pressure. LiOH _((aq)) (3 M, 1 mL) was added to the residue which had been dissolved in THF (1 mL) and MeOH (1 mL) and the mixture was heated at 50° C. for 24 hours. Water (5 mL) was then added, and the pH of the mixture was adjusted to pH 3-4 by adding a solution of 1 M aqueous HCl. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (150 mg, 31%). MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.2; m/z found, 688.3 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.18 (m, 2H), 7.93 (d, J=2.3 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 6.96 (s, 1H), 4.83 (s, 1H), 4.50-4.22 (m, 2H), 3.77-3.64 (m, 2H), 3.33-3.24 (m, 2H), 3.20-3.02 (m, 2H), 2.55 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H), 1.44-1.33 (m, 2H), 1.26 (s, 3H), 1.16 (s, 3H), 1.12-1.02 (m, 2H).

Example 18: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid enantiomers (Example 17, 150 mg) was separated by chiral SFC (stationary phase: Chiralcel OZ-H 2×25 cm, mobile phase: 60% CO₂, 40% MeOH) to afford two enantiomers. The first eluting enantiomer (68 mg) was designated (*S). MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.2; m/z found, 688.3 [M+H]⁺.

Example 19: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (53 mg) from the separation of isomers by chiral SFC described in Example 18 was designated (*R). MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.2; m/z found, 688.3 [M+H]⁺.

Example 20: 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid and its trifluoroacetic acid salt

DMF (1.4 mL) was added to a mixture of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 67 mg, 0.28 mmol) and sodium hydride (60% dispersion in mineral oil, 24 mg, 0.60 mmol) under nitrogen at 0° C. After 10 minutes, a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 31, 0.7 ml, 0.4 M in DMF, 0.3 mmol) was added and the mixture was allowed to warm to room temperature for 2.5 hours. 1 M Aqueous sodium hydroxide solution (0.84 mL) was added and the reaction was stirred at room temperature overnight. An additional portion of 1 M aqueous sodium hydroxide (0.56 mL) was added and the reaction was stirred again overnight at room temperature. The mixture was filtered and the filtrate was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). The pure fractions resulting from the preparative acidic HPLC were collected and lyophilized to dryness to provide the title compound (108.2 mg, 67%) as its trifluoroacetic acid salt. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.4 [M+H]⁺.

Example 21: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of 3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 20, 108.2 mg) was separated by chiral SFC (stationary phase: Chiralcel OJ-H 5 μm, 250×20 mm, mobile phase: 80% CO₂, 20% MeOH) to afford two diastereomers. The first eluting isomer (44 mg) was designated (*S). MS: mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.0. ¹H NMR (400 MHz, CDCl₃) δ 8.25-8.16 (m, 2H), 7.30-7.24 (m, 2H), 7.04-6.98 (m, 2H), 6.98-6.92 (m, 1H), 6.87-6.80 (m, 1H), 4.82-4.69 (m, 2H), 4.64-4.44 (m, 2H), 4.38-4.29 (m, 1H), 4.23-4.12 (m, 1H), 3.65-3.50 (m, 2H), 3.33-3.24 (m, 1H), 3.10-2.89 (m, 2H), 2.89-2.75 (m, 1H), 2.68 (s, 3H), 2.19 (s, 3H), 2.00-1.88 (m, 1H), 1.85-1.73 (m, 1H), 1.62-1.43 (m, 3H), 1.30-1.22 (m, 1H), 1.22-1.13 (m, 1H).

Example 22: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (41 mg) from the separation of isomers by chiral SFC described in Example 21 was designated (*R). MS: mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.0. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (dd, J=4.8, 1.9 Hz, 1H), 8.07 (dd, J=7.7, 1.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.11-7.06 (m, 3H), 6.80 (dd, J=7.7, 4.8 Hz, 1H), 4.95 (t, J=7.9 Hz, 1H), 4.64 (q, J=7.3 Hz, 2H), 4.61-4.53 (m, 1H), 4.39 (d, J=14.3 Hz, 1H), 4.13 (d, J=14.2 Hz, 1H), 3.66-3.59 (m, 1H), 3.56-3.49 (m, 1H), 3.32-3.24 (m, 1H), 3.18-3.04 (m, 3H), 2.82 (s, 3H), 2.26 (s, 3H), 2.00-1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.65-1.58 (m, 4H), 1.47-1.40 (m, 1H).

Example 23: 3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

DMF (0.75 mL) was added to a mixture of (*R)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 12, 75 mg, 0.29 mmol) and sodium hydride (60% dispersion in mineral oil, 38 mg, 0.95 mmol) under nitrogen at 0° C. After 10 minutes, a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 32, 0.75 ml, 0.4 M in DMF, 0.29 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was filtered and the filtrate was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). The pure fractions resulting from the preparative acidic HPLC were collected and lyophilized to dryness to provide the title compound. (104.7 mg, 59%). MS (ESI): mass calcd. for C₃₁H₃₄N₆O₅S, 602.2; m/z found, 603.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.37-8.30 (m, 1H), 8.21-8.16 (m, 1H), 7.54-7.49 (m, 0.5H), 7.49-7.44 (m, 0.5H), 7.44-7.40 (m, 0.5H), 7.40-7.34 (m, 0.5H), 7.31-7.28 (m, 0.5H), 7.21-7.17 (m, 0.5H), 7.09-7.02 (m, 1.5H), 7.00-6.93 (m, 1H), 6.87-6.83 (m, 0.5H), 4.96-4.86 (m, 1H), 4.72-4.63 (m, 0.5H), 4.58-4.49 (m, 1.5H), 4.47-4.40 (m, 0.5H), 4.34-4.16 (m, 2H), 3.88-3.82 (m, 0.5H), 3.81-3.63 (m, 5H), 3.30-3.18 (m, 1.5H), 3.18-3.04 (m, 1H), 3.04-2.91 (m, 1.5H), 2.80 (s, 1.5H), 2.69 (s, 1.5H), 2.20 (s, 1.5H), 2.12 (s, 1.5H), 1.40-1.24 (m, 4H).

Example 24: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 23, 104.7 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 2×25 cm, mobile phase: 60% CO₂, 40% MeOH) to afford two diastereomers. The first eluting isomer (34 mg) was designated (*S). MS: mass calcd. for C₃₁H₃₄N₆O₅S, 602.2; m/z found, 603.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30-8.26 (m, 1H), 8.11-8.06 (m, 1H), 7.46-7.42 (m, 1H), 7.40-7.36 (m, 1H), 7.22 (s, 1H), 7.08-7.02 (m, 2H), 6.89-6.84 (m, 1H), 4.95-4.89 (m, 1H), 4.59-4.49 (m, 2H), 4.38-4.31 (m, 1H), 4.28 (d, J=13.8 Hz, 1H), 3.93-3.85 (m, 1H), 3.76-3.59 (m, 5H), 3.26-3.20 (m, 1H), 3.20-3.11 (m, 1H), 3.01-2.88 (m, 2H), 2.82 (s, 3H), 2.08 (s, 3H), 1.35-1.29 (m, 2H), 1.29-1.23 (m, 2H).

Example 25: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (36 mg) from the separation of isomers by chiral SFC described in Example 24 was designated (*R). MS: mass calcd. for C₃₁H₃₄N₆O₅S, 602.2; m/z found, 603.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.35-8.29 (m, 1H), 8.13-8.07 (m, 1H), 7.57-7.49 (m, 1H), 7.46-7.40 (m, 1H), 7.36-7.32 (m, 1H), 7.07-7.00 (m, 1H), 6.95-6.87 (m, 1H), 6.83-6.76 (m, 1H), 4.91 (dd, J=11.9, 3.8 Hz, 1H), 4.75-4.69 (m, 1H), 4.66-4.54 (m, 2H), 4.39-4.34 (m, 1H), 4.18 (d, J=13.1 Hz, 1H), 3.83-3.70 (m, 5H), 3.35-3.27 (m, 1H), 3.20 (dd, J=13.5, 4.1 Hz, 1H), 3.11-3.04 (m, 1H), 3.01-2.93 (m, 1H), 2.69 (s, 3H), 2.20 (s, 3H), 1.39-1.24 (m, 4H).

Example 26: (*S)-3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 122 mg, 0.289 mmol), 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7, 87 mg, 0.36 mmol), and triphenylphosphine (116 mg, 0.444 mmol) in THF (4.5 mL) was stirred at room temperature for 1 minute. DBAD (107 mg, 0.465 mmol) was added and the solution was stirred at room temperature for 20 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (0 to 20% ethyl acetate/DCM, gradient elution) to afford the title compound (550 mg) which was contaminated with triphenylphosphine oxide byproduct and remaining solvent. MS (ESI): mass calcd. for C₃₁H₃₁F₃N₄O₆S, 644.2; m/z found, 645.3 [M+H]⁺.

Step B: ((*S)-3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Aqueous sodium hydroxide (1 M, 2.5 mL, 2.5 mmol) was added to a solution of ethyl (*S)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (540 mg, 0.84 mmol) in THF (4 mL) and ethanol (1 mL). The reaction was stirred at room temperature for 4 hours, then concentrated under reduced pressure to remove THF. A small amount of DMF was added to form a solution, and the reaction was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). The pure fractions resulting from the preparative basic HPLC were collected and lyophilized to dryness to provide the title compound (88.2 mg, 17%). MS (ESI): mass calcd. for C₂₉H₂₇F₃N₄O₆S, 616.2; m/z found, 617.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=7.2 Hz, 1H), 7.87 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.55 (m, 1H), 7.37 (dd, J=8.1, 1.2 Hz, 1H), 7.34-7.29 (m, 1H), 7.25-7.22 (m, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.98-6.93 (m, 2H), 4.91-4.84 (m, 1H), 4.71-4.63 (m, 2H), 4.52-4.45 (m, 1H), 4.32-4.22 (m, 3H), 3.87-3.80 (m, 1H), 3.76-3.70 (m, 1H), 3.08-3.01 (m, 1H), 2.96-2.88 (m, 1H), 2.73 (s, 3H), 2.26 (s, 3H).

Example 27: (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (254 mg, 85%) was prepared using analogous conditions as described in Example 26, Step A where 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 8) was used instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7) and (0 to 80% ethyl acetate/hexanes, gradient elution) was used for flash column chromatography instead of (0 to 20% ethyl acetate/DCM, gradient elution). MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.2; m/z found, 644.2 [M+H]⁺.

Step B: (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Aqueous sodium hydroxide (1 M, 1.2 mL, 1.2 mmol) was added to a solution of ethyl (*S)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (254 mg, 0.395 mmol) in THF (2 mL) and ethanol (0.2 mL). The reaction was stirred at 50° C. for 1 hour, then concentrated under a stream of nitrogen to remove THF. 1 M Aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). The pure fractions resulting from the preparative basic HPLC were collected and lyophilized to dryness to provide the title compound (125 mg, 51%). MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅O₅S, 615.2; m/z found, 616.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (d, J=7.1 Hz, 1H), 8.34-8.32 (m, 1H), 8.10-8.07 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7.09 (m, 3H), 4.80 (t, J=7.8 Hz, 1H), 4.26-4.12 (m, 2H), 3.64-3.49 (m, 1H), 3.10-2.96 (m, 2H), 2.70 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H), 0.97-0.85 (m, 2H), 0.64-0.52 (m, 2H).

Example 28: 3-(3-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: 7-Bromo-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. 2,2-Difluoroacetic anhydride (34.50 g, 197.9 mmol) was added slowly to 4-bromo-2-hydrazinyl-3-methylpyridine (Intermediate 23, 2.00 g, 9.99 mmol). The reaction initially started to reflux and the solids turned yellow, but within 5 minutes the reaction was homogeneous. The reaction mixture was warmed to 50° C. After 18 hours, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (100 mL) was added, followed by aqueous saturated NaHCO₃ solution until pH was about 7-8. The layers were separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% ethyl acetate/hexanes, gradient elution) to afford the title compound (2.5 g, 96%) as a white solid. MS (ESI): mass calcd. for C₈H₆BrF₂N₃, 261.0; m/z found, 262.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=7.2 Hz, 1H), 7.18-7.09 (m, 2H), 2.76 (d, J=0.8 Hz, 3H).

Step B: Ethyl (E)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. A mixture containing 7-bromo-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (2.50 g, 9.54 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2.66 g, 11.77 mmol), potassium carbonate (2.64 g, 19.1 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), complex with dichloromethane (1:1) (705 mg, 0.96 mml) in 1,4-dioxane (33 mL) and water (10 mL) was sparged with N₂ for 15 minutes. The mixture was then heated to 90° C. After one hour, the reaction was allowed to cool to room temperature and filtered through diatomaceous earth such as Celite® and washed with ethyl acetate (100 mL). Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% ethyl acetate/hexanes, gradient elution) to provide the title compound (1.58 g, 59%) as a reddish brown solid. MS (ESI): mass calcd. for C₁₃H₆F₂N₃O₂, 281.3; m/z found, 282.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=7.3 Hz, 1H), 8.00 (d, J=15.9 Hz, 1H), 7.48-7.07 (m, 2H), 6.51 (d, J=15.9 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.84 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).

Step C: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. TEA (1.18 mL, 8.50 mmol) and [Rh(COD)Cl]₂ (143 mg, 0.29 mmol) were added sequentially to a slurry of ethyl (E)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (1.58 g, 5.62 mmol) and (3-(hydroxymethyl)-4-methylphenyl)boronic acid (1.41 g, 8.50 mmol) in 1,4-dioxane (30 mL) and water (15 mL).

The reaction mixture was heated to 95° C. After 45 minutes, the reaction was allowed to cool to room temperature and a mixture of ethyl acetate/water was added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0 to 100% ethyl acetate/hexanes, gradient elution) to afford the title compound (1.80 g, 79%) as a yellow foam. MS (ESI): mass calcd. for C₂₁H₂₃F₂N₃O₃, 403.4; m/z found, 404.2 [M+H]⁺.

Step D: Ethyl 3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.72 mL, 3.67 mmol) was added to a mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (900 mg, 2.23 mmol), 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 9, 882 mg, 3.17 mmol) and triphenylphosphine (868 mg, 3.31 mmol) in THF (25 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organics were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% ethyl acetate/hexanes, gradient elution) to provide the title compound (1.40 g, 95%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₅F₂N₇O₄S, 663.7; m/z found, 664.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=2.1 Hz, 1H), 8.27-8.14 (m, 2H), 7.24-7.09 (m, 2H), 7.14-7.06 (m, 1H), 6.86 (dd, J=9.9, 7.2 Hz, 1H), 4.95 (ddd, J=8.6, 7.1, 4.0 Hz, 1H), 4.70-4.60 (m, 1H), 4.50 (dd, J=14.6, 11.8 Hz, 1H), 4.34 (ddt, J=13.9, 9.7, 4.9 Hz, 1H), 4.22-4.02 (m, 4H), 3.38-3.07 (m, 4H), 3.02 (ddd, J=15.7, 8.7, 5.5 Hz, 1H), 2.83 (d, J=7.6 Hz, 3H), 2.24 (d, J=10.5 Hz, 3H), 1.74-1.68 (m, 1H), 1.64-1.43 (m, 1H), 1.47-1.31 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.18 (td, J=7.2, 2.0 Hz, 3H).

Step E: 3-(3-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.40 g, 2.10 mmol), 1 M aqueous NaOH solution (10.0 mL, 10.0 mmol), and THF (10 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (0 to 10% MeOH/DCM, gradient elution) to provide the title compound (1.27 g, 95%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₁F₂N₇O₄S, 635.6; m/z found, 636.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (dd, J=2.2, 1.2 Hz, 1H), 8.23 (dd, J=2.2, 0.9 Hz, 1H), 8.21-8.09 (m, 1H), 7.14 (ddt, J=15.9, 7.2, 4.2 Hz, 3H), 6.90 (dd, J=11.4, 7.3 Hz, 1H), 4.99-4.90 (m, 1H), 4.65 (s, 1H), 4.57 (s, 3H), 4.48 (t, J=14.5 Hz, 1H), 4.33 (tt, J=13.3, 5.0 Hz, 1H), 4.16 (dd, J=24.2, 14.8 Hz, 1H), 3.37 (dd, J=13.3, 3.5 Hz, 1H), 3.31-3.19 (m, 1H), 3.19 (dt, J=6.1, 4.4 Hz, 1H), 3.20-3.12 (m, 1H), 3.07 (dt, J=16.0, 8.9 Hz, 1H), 2.76 (d, J=7.5 Hz, 3H), 2.23 (d, J=12.8 Hz, 3H), 1.77-1.61 (m, 3H), 1.55-1.41 (m, 1H), 1.36 (m, 1H).

Example 29: (*R)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 4 diasteroisomers of 3-(3-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 28, 1.27 g) were separated using two chiral separation methods. The mixture of 4 diastereomers was initially subjected to Chiral Separation Method I: chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 45% CO₂, 55% EtOH) to provide Example 29 and Example 30 and a mixture of the two remaining diastereomers (Example 31 and Example 32). The mixture of Example 31 and Example 32 was subsequently separated using Chiral Separation Method II: chiral SFC (stationary phase: Chiralpak IG 5 μm 250×20 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford Example 31 and Example 32. The separation of isomers by Chiral Separation Method, order of elution and designated stereochemistry is tabulated below in Table 2. When the stereochemical configuration is written as, for example (*R, *S), with the first configuration, (*R), corresponds to the configuration at the 3-propanoic carbon and the second configuration, (*S), corresponds to the stereochemistry at the sultam. The characterization for (*R)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 29) is as follows: MS (ESI): mass calcd. for C₃₁H₃₁F₂N₇O₄S, 635.6; m/z found, 636.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47 (d, J=2.2 Hz, 1H), 8.25 (d, J=2.2 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.18-7.06 (m, 3H), 6.90 (d, J=7.3 Hz, 1H), 4.89 (t, J=7.8 Hz, 1H), 4.46 (d, J=15.0 Hz, 1H), 4.35 (dt, J=13.4, 4.9 Hz, 1H), 4.19 (d, J=15.1 Hz, 1H), 3.40 (dd, J=13.3, 3.5 Hz, 1H), 3.34 (s, 2H), 3.26-3.11 (m, 2H), 3.04 (dd, J=15.6, 6.8 Hz, 1H), 2.94 (dd, J=15.6, 8.9 Hz, 1H), 2.78 (s, 3H), 2.22 (s, 3H), 1.77-1.70 (m, 1H), 1.65 (d, J=6.1 Hz, 1H), 1.56-1.42 (m, 2H), 1.03 (d, J=6.3 Hz, 3H).

TABLE 2 Chiral separation method, Order of elution and Designated stereochemistry for Examples 29-32 Chiral Separation Example # method/order of elution Configuration 29 Method I, first eluting (*R, *S) 30 Method I, second eluting (*R, *R) 31 Method II, first eluting (*S, *S) 32 Method II, second eluting (*S, *R)

Example 30: (*R)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (351 mg) was obtained as described in Example 29 and Table 2: MS (ESI): mass calcd. for C₃₁H₃₁F₂N₇O₄S, 635.6; m/z found, 636.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.3 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.15 (d, J=6.6 Hz, 1H), 7.21-7.07 (m, 4H), 6.85 (d, J=7.0 Hz, 1H), 4.94 (s, 1H), 4.62 (dd, J=12.0, 5.2 Hz, 1H), 4.49 (d, J=14.7 Hz, 1H), 4.30 (dt, J=13.7, 5.2 Hz, 1H), 4.20 (d, J=14.7 Hz, 1H), 3.82 (s, 2H), 3.49 (s, 1H), 3.32-3.09 (m, 2H), 3.01 (s, 1H), 2.78 (s, 3H), 2.26 (s, 3H), 1.70 (dt, J=15.3, 5.7 Hz, 1H), 1.64-1.57 (m, 1H), 1.54-1.41 (m, 3H), 1.04 (s, 1H).

Example 31: (*S)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (199 mg) was obtained as described in Example 29 and Table 2: MS (ESI): mass calcd. for C₃₁H₃₁F₂N₇O₄S, 635.6; m/z found, 636.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47 (d, J=2.1 Hz, 1H), 8.25 (d, J=2.2 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.13 (ddd, J=23.3, 5.8, 3.6 Hz, 3H), 6.89 (d, J=7.3 Hz, 1H), 4.93 (dd, J=9.0, 6.6 Hz, 1H), 4.71-4.63 (m, 1H), 4.57 (s, 3H), 4.47 (d, J=15.0 Hz, 1H), 4.35 (dt, J=13.5, 4.9 Hz, 1H), 4.19 (d, J=15.0 Hz, 1H), 3.38 (dd, J=13.3, 3.6 Hz, 1H), 3.26-3.11 (m, 2H), 3.04 (dd, J=15.9, 9.1 Hz, 1H), 2.78 (s, 3H), 2.23 (s, 3H), 1.74 (s, 2H), 1.64 (t, J=6.9 Hz, 1H), 1.54 (d, J=6.9 Hz, 1H), 1.52-1.41 (m, 1H), 1.00 (d, J=5.9 Hz, 1H).

Example 32: (*S)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (260 mg) was obtained as described in Example 29 and Table 2: MS (ESI): mass calcd. for C₃₁H₃₁F₂N₇O₄S, 635.6; m/z found, 636.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.3 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.15 (d, J=6.6 Hz, 1H), 7.21-7.07 (m, 3H), 6.85 (d, J=7.0 Hz, 1H), 4.94 (s, 1H), 4.62 (dd, J=12.0, 5.2 Hz, 1H), 4.49 (d, J=14.7 Hz, 1H), 4.30 (dt, J=13.7, 5.2 Hz, 1H), 4.20 (d, J=14.7 Hz, 1H), 3.49 (s, 1H), 3.32-3.09 (m, 5H), 3.01 (s, 1H), 2.78 (s, 3H), 2.26 (s, 3H), 1.70 (dt, J=15.3, 5.7 Hz, 1H), 1.64-1.57 (m, 1H), 1.54-1.41 (m, 3H), 1.04 (s, 1H).

Example 33: 3-(6-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A mixture of 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 30, 500 mg, 1.53 mmol), ethyl (Z)-3-(6-(acetoxymethyl)-5-methylpyridin-2-yl)acrylate (Intermediate 15, 268 mg, 1.02 mmol), potassium carbonate (434 mg, 3.14 mmol), [Rh(COD)Cl]₂ (51 mg, 0.10 mmol), THF (6 mL) and propan-2-ol (0.08 mL) was sparged with N₂ for 15 minutes. The mixture was then heated to 95° C. After one hour, the reaction was allowed to cool to room temperature, filtered through diatomaceous earth such as Celite®, which was rinsed with ethyl acetate (10 mL). Brine was added to the filtrate and the layers were separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% EtOAc/hexanes, gradient elution) to afford the title compound (125 mg, 26%) as a reddish brown solid. MS (ESI): mass calcd. for C₂₂H₂₃F₃N₄O₄, 464.4; m/z found, 465.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.31 (d, J=7.2 Hz, 1H), 7.60 (dd, J=7.8, 0.9 Hz, 1H), 7.25 (dd, J=7.6, 3.9 Hz, 2H), 5.31-5.21 (m, 2H), 5.13 (t, J=7.7 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.42 (dd, J=16.5, 8.0 Hz, 1H), 3.10 (dd, J=16.5, 7.4 Hz, 1H), 2.84 (d, J=0.7 Hz, 3H), 2.33 (s, 3H), 2.13 (s, 3H), 1.14 (t, J=7.1 Hz, 3H).

Step B: Ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Potassium carbonate (304 mg, 2.2 mmol) was added to a solution of ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (390 mg, 0.868 mmol) in THF (10 mL) and ethanol (7 mL) at room temperature. The reaction mixture was heated to 50° C. After 16 hours, the mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% EtOAc/hexanes, gradient elution) to provide the title compound (700 mg, 96%) as a clear oil. MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.4; m/z found, 422.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=7.2 Hz, 1H), 7.35 (dd, J=1.9, 0.9 Hz, 1H), 7.11-6.98 (m, 3H), 4.93 (dd, J=9.3, 6.5 Hz, 1H), 4.64 (d, J=4.9 Hz, 2H), 4.11-3.96 (m, 3H), 3.76 (p, J=5.0 Hz, 1H), 3.13 (dd, J=15.9, 6.5 Hz, 1H), 2.80 (s, 3H), 2.21 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).

Step C: Ethyl 3-(6-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (264 mg, 1.15 mmol) was added to a mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (320 mg, 0.76 mmol), 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 9, 253 mg, 0.91 mmol), and triphenylphosphine (299 mg, 1.14 mmol) in THF (25 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0 to 100% EtOAc/hexanes, gradient elution) to provide the title compound (510 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₃F₃N₈O₄S, 682.7; m/z found, 683.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (t, J=2.3 Hz, 1H), 8.21 (dd, J=8.9, 2.2 Hz, 1H), 8.00 (dd, J=7.2, 5.1 Hz, 1H), 7.43 (dd, J=17.0, 7.9 Hz, 1H), 7.38-7.25 (m, 1H), 7.12 (dd, J=22.9, 7.8 Hz, 1H), 5.03 (q, J=7.4 Hz, 1H), 4.86-4.64 (m, 2H), 4.54-4.39 (m, 1H), 4.26 (dd, J=26.6, 14.9 Hz, 1H), 4.15-3.96 (m, 1H), 3.68 (dd, J=12.8, 3.6 Hz, 1H), 3.62-3.47 (m, 2H), 3.47-3.27 (m, 2H), 3.04 (ddd, J=28.8, 16.4, 7.4 Hz, 1H), 2.88 (d, J=2.8 Hz, 3H), 2.25 (d, J=24.5 Hz, 4H), 1.79 (qt, J=15.2, 5.6 Hz, 3H), 1.62 (dq, J=10.7, 5.4 Hz, 1H), 1.58-1.41 (m, 1H), 1.15 (td, J=7.1, 1.0 Hz, 3H).

Step D: 3-(6-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (510 mg, 0.75 mmol), 1 M aqueous NaOH solution (2.2 mL, 2.2 mmol), and THF (3 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organics were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (0 to 10% MeOH/DCM, gradient elution) to provide the title compound (477 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₃₀H₂₉F₃N₈O₄S, 654.2; m/z found, 655.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.14 (s, 1H), 8.46 (dd, J=4.5, 2.2 Hz, 1H), 8.23 (dd, J=10.3, 2.2 Hz, 1H), 8.02 (dd, J=9.6, 7.1 Hz, 1H), 7.50-7.37 (m, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.10 (dd, J=21.8, 7.8 Hz, 1H), 5.05 (q, J=7.4 Hz, 1H), 4.88-4.68 (m, 2H), 4.49 (tt, J=13.1, 4.8 Hz, 1H), 4.34 (d, J=16.0 Hz, 1H), 3.78 (dd, J=12.9, 3.5 Hz, 1H), 3.68 (dd, J=16.6, 8.3 Hz, 1H), 3.63-3.31 (m, 3H), 3.17-3.01 (m, 1H), 2.86 (d, J=4.1 Hz, 3H), 2.23 (s, 3H), 1.82 (dq, J=13.8, 6.6 Hz, 2H), 1.79-1.63 (m, 1H), 1.67-1.59 (m, 1H), 1.63-1.44 (m, 1H).

Example 34: (*S)-3-(6-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 4 diasteroisomers of 3-(6-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 33) were separated using two chiral separation methods. The mixture of 4 diastereomers was initially subjected to Chiral Separation Method III: chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 45% CO₂, 55% EtOH) to provide Example 34 and Example 35 and a mixture of the two remaining diastereomers Example 36 and Example 37. The mixture of Example 36 and Example 37 was subsequently separated using Chiral Separation Method IV: chiral SFC (stationary phase: Chiralpak AS-H 5 μm 250×20 mm, Mobile phase: 70% CO₂, 30% EtOH) to afford Example 36 and Example 37. The chiral separation method, order of elution and designated stereochemistry is tabulated below in Table 3. When the stereochemical configuration is written as, for example (*R, *S), with the first configuration, (*R), corresponds to the configuration at the 3-propanoic carbon and the second configuration, (*S), corresponds to the stereochemistry at the sultam. The characterization for (*S)-3-(6-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (264 mg) is as follows: MS (ESI): mass calcd. for C₃₀H₂₉F₃N₈O₄S, 654.2; m/z found, 655.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, J=2.2 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 5.03 (t, J=7.4 Hz, 1H), 4.85-4.76 (m, 2H), 4.50 (dt, J=13.5, 4.8 Hz, 1H), 4.30 (d, J=16.0 Hz, 1H), 3.75 (dd, J=12.7, 3.5 Hz, 1H), 3.63 (dd, J=16.6, 8.2 Hz, 1H), 3.52 (t, J=12.7 Hz, 1H), 3.37 (ddd, J=14.0, 9.1, 5.6 Hz, 1H), 3.03 (dd, J=16.5, 6.6 Hz, 1H), 2.87 (s, 3H), 2.23 (s, 3H), 1.86-1.77 (m, 3H), 1.63 (dd, J=12.8, 7.0 Hz, 3H), 1.48 (d, J=18.2 Hz, 1H).

TABLE 3 Chiral separation method, Order of elution and Designated stereochemistry for Examples 34-37 Chiral Separation Example # method/order of elution Configuration 34 Method III, first eluting (*S, *S) 35 Method III, second eluting (*S, *R) 36 Method IV, first eluting (*R, *R) 37 Method IV, second eluting (*R, *S)

Example 35: (*S)-3-(6-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (114 mg) was obtained as described in Example 34 and Table 3: MS (ESI): mass calcd. for C₃₀H₂₉F₃N₈O₄S, 654.2; m/z found, 655.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.1 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 4.99 (t, J=7.3 Hz, 1H), 4.75 (d, J=14.7 Hz, 2H), 4.47 (dt, J=13.5, 4.8 Hz, 1H), 4.22 (d, J=14.5 Hz, 1H), 3.72 (q, J=7.0 Hz, 1H), 3.54-3.35 (m, 4H), 3.05 (dd, J=16.4, 7.2 Hz, 1H), 2.86 (s, 3H), 2.30 (s, 3H), 1.80 (d, J=6.8 Hz, 1H), 1.80 (s, 2H), 1.81-1.70 (m, 1H), 1.59-1.45 (m, 1H), 1.24 (t, J=7.0 Hz, 1H).

Example 36: (*R)-3-(6-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (95 mg) was obtained as described in Example 34 and Table 3: MS (ESI): mass calcd. for C₃₀H₂₉F₃N₈O₄S, 654.2; m/z found, 655.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.2 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.40 (dd, J=7.8, 0.8 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 5.07-5.00 (m, 1H), 4.80 (dd, J=16.4, 10.8 Hz, 2H), 4.51 (dt, J=13.6, 4.8 Hz, 1H), 4.30 (d, J=16.0 Hz, 1H), 3.78-3.68 (m, 2H), 3.64 (dd, J=16.5, 8.3 Hz, 1H), 3.56-3.47 (m, 1H), 3.37 (ddd, J=13.5, 9.1, 5.7 Hz, 1H), 3.02 (dd, J=16.5, 6.5 Hz, 1H), 2.88 (s, 3H), 2.24 (s, 3H), 1.86-1.78 (m, 4H), 1.64 (d, J=5.8 Hz, 1H), 1.24 (t, J=7.0 Hz, 1H).

Example 37: (*R)-3-(6-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (128 mg) was obtained as described in Example 34 and Table 3: MS (ESI): mass calcd. for C₃₀H₂₉F₃N₈O₄S, 654.2; m/z found, 655.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.2 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.47-7.42 (m, 1H), 7.19 (d, J=7.3 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.00 (t, J=7.4 Hz, 1H), 4.80-4.71 (m, 2H), 4.47 (dt, J=13.5, 4.8 Hz, 1H), 4.22 (d, J=14.4 Hz, 1H), 3.73 (q, J=7.0 Hz, 1H), 3.56-3.33 (m, 4H), 3.08 (dd, J=16.5, 7.3 Hz, 1H), 2.86 (s, 3H), 2.31 (s, 3H), 1.85-1.70 (m, 4H), 1.58-1.45 (m, 1H), 1.24 (t, J=7.1 Hz, 1H).

Example 38: (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: 74(6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in THF (8 mL, 10.4 mmol) was added dropwise to a stirring solution of 7-iodo-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridine (Intermediate 53, 3.3 g, 10.1 mmol) in THF (25 mL) at 20° C. After 15 minutes, the Grignard solution was added by cannula to a stirring solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (Intermediate 57, 2.5 g, 9.2 mmol) in THF (25 mL) at 20° C. After 20 minutes, during which time the bath temperature rose to 10° C., methanol (5 mL) was added. The round-bottomed flask was removed from the cooling bath and allowed to warm to room temperature. The pH of the mixture was adjusted to 7 by adding 1 M aqueous HCl solution and then partitioned between water and ethyl acetate. The layers were separated. The aqueous layer was extracted with ethyl acetate which resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide a yellow oil. The oil was dissolved in dichloromethane (44 mL) and then cooled in an ice-water bath; whereupon 2,6-di-tert-butylpyridine (3 mL, 13.4 mmol) and thionyl chloride (0.9 mL, 12.4 mmol) were added sequentially. The round-bottomed flask was removed from the cooling bath and allowed to warm to room temperature over 45 minutes. Saturated aqueous NaHCO₃was added until the pH of the mixture was 7. The mixture was then poured into water and the aqueous layer extracted with dichloromethane which resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (hexanes-ethyl acetate) to afford the title compound (3.87 g, 87%). MS (ESI): mass calcd. for C₂₂H₂₈ClF₃N₄OSi, 484.2; m/z found, 485.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=7.3 Hz, 1H), 7.55-7.45 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 6.42 (s, 1H), 4.72 (s, 2H), 2.86 (s, 3H), 2.39 (s, 3H), 0.79 (s, 9H) 0.06 (s, 3H), 0.09 (s, 3H).

Step B: Methyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Indium tribromide (151 mg, 0.426 mmol) was added to a stirring mixture of 7-((6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (730 mg, 1.5 mmol) and methyl trimethylsilyl dimethylketene acetal (1.3 mL, 6.0 mmol) in dichloromethane (7.5 mL). After 16 hours, ethyl acetate and saturated aqueous NaCl solution were added and the resulting biphasic mixture was separated. The organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford a residue. The residue was purified by flash column chromatography (hexanes-ethyl acetate) to afford the title compound which was contaminated with other by-products (406 mg). This material was taken onto the next step without further purification of characterization. MS (ESI): mass calcd. for C₂₇H₃₇F₃N₄O₃Si, 550.3; m/z found, 551.2 [M+H]⁺.

Step C: Methyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A 1 M solution of TBAF in THF (1.2 mL, 1.2 mmol) was added to a stirring solution of the impure methyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (406 mg) in THF (4 mL). After 5 minutes, the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford a residue. The residue was purified by RP-HPLC (SunFire Prep C18 OBD column, 5 μM, 30×250 mm, eluting with acetonitrile-water w/0.05% TFA. The pure fractions were combined and lyophilized to afford the title compound as an off-white powder (197 mg, 61%). MS (ESI): mass calcd. for C₂₁H₂₃F₃N₄O₃, 436.2; m/z found, 437.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (d, J=7.2 Hz, 1H), 7.47-7.43 (m, 1H), 7.11 (d, J=7.4 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 5.04 (s, 1H), 4.71-4.63 (m, 1H), 4.60 (d, J=5.2 Hz, 2H), 3.55 (s, 3H), 2.79 (s, 3H), 2.24 (s, 3H), 1.31 (s, 3H), 1.22 (s, 3H).

Step D: Methyl 3-(6-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Di-tert-butyl azodicarboxylate (135 mg, 0.587 mmol) was added in one portion to a stirring mixture containing methyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (197 mg, 0.451 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 160 mg, 0.592 mmol), and triphenylphosphine (151 mg, 0.576 mmol) in THF (3 mL) and DMF (2 mL). After 12 hours, the mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford a residue. The residue was purified by three sequential chromatographic steps: first by flash column chromatography (hexanes-ethyl acetate), second by flash column chromatography (dichloromethane-methanol) and third by RP-HPLC (XBridge Prep OBD C18 column, 5 μm, 50×250 mm, eluent: 20 mM aqueous NH₃-acetonitrile) to afford the title compound as a white foam (250 mg, 80%). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58-8.54 (m, 1H), 8.27 (d, J=7.3 Hz, 1H), 8.20 (dd, J=7.6, 2.0 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, J=7.6, 4.9 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.99 (s, 1H), 4.68-4.49 (m, 2H), 3.94-3.70 (m, 4H), 3.66-3.54 (m, 2H), 3.51 (s, 3H), 2.78 (s, 3H), 2.24 (s, 3H), 1.80-1.53 (m, 4H), 1.38 (s, 3H), 1.30 (s, 3H).

Step E: (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing methyl 3-(6-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (250 mg, 0.363 mmol), 2 M aqueous lithium hydroxide solution (1.5 mL, 3 mmol), THF (3 mL), and methanol (3 mL) was stirred at 60° C. After 12 hours, the reaction mixture was cooled to room temperature, diluted with water, and brought to pH 4-5 by dropwise addition of 1 M aqueous HCl solution. The mixture was extracted with ethyl acetate which resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide a mixture of 3-(6-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (245 mg). These isomers were separated by chiral SFC (stationary phase: Chiralpak AD-H, 250×20 mm, mobile phase: 80% CO₂, 20% EtOH) to afford two enantiomers. The first eluting isomer (115 mg) was designated (*S). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.58-8.54 (m, 1H), 8.27 (d, J=7.3 Hz, 1H), 8.20 (dd, J=7.6, 1.9 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.26 (d, J=7.8 Hz, 1H), 4.99 (s, 1H), 4.59 (s, 2H), 3.91-3.69 (m, 4H), 3.65-3.53 (m, 2H), 2.78 (s, 3H), 2.24 (s, 3H), 1.77-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.34 (s, 3H), 1.31 (s, 3H).

Example 39: (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (112 mg) from the separation of isomers by chiral SFC described in Example 38 was designated (*R). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.1 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.56 (dd, J=4.9, 1.9 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 8.21-8.18 (m, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.26 (d, J=7.8 Hz, 1H), 4.99 (s, 1H), 4.59 (s, 2H), 3.92-3.69 (m, 4H), 3.65-3.52 (m, 2H), 2.78 (s, 3H), 2.24 (s, 3H), 1.77-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H).

Example 40: (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

Step A: Methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate. A solution of methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 55, 145 mg, 0.36 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 146 mg, 0.54 mmol), and triphenylphosphine (153 mg, 0.58 mmol) in THF (2 mL) and DMF (2 ml) was stirred at room temperature for 5 minutes. DBAD (131 mg, 0.57 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (0-10% MeOH/DCM, gradient elution) to afford the title compound (174 mg, 74%). MS (ESI): mass calcd. for C₃₅H₄₁N₅O₆S, 659.3; m/z found, 660.4 [M+H]⁺.

Step B: (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid. 2 M Aqueous lithium hydroxide (0.54 mL, 1.1 mmol) was added to a solution of methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (70 mg, 0.1 mmol) in MeOH (0.6 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product, (35 mg), was purified by preparative acidic HPLC (XBridge C18, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₄H₃₉N₅O₆S, 645.2; m/z found, 646.3 [M+H]⁺.

Example 41: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The mixture of 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid isomers (Example 40) was separated by chiral SFC (Chiralcel OJ-H, 2×25 cm, mobile phase: 80% CO₂, 20% MeOH with 0.1% diethylamine) to afford two enantiomers. The first eluting isomer (11 mg) was designated (*S): MS: mass calcd. for C₃₄H₃₉N₅O₆S, 645.3; m/z found, 646.2. ¹H NMR (400 MHz, CDCl₃) δ 8.50-8.44 (m, 1H), 8.22-8.17 (m, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.25-7.22 (m, 1H), 7.21-7.15 (m, 2H), 7.05 (d, J=7.6 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 4.89 (s, 1H), 4.56-4.35 (m, 2H), 4.06-3.92 (m, 2H), 3.67-3.32 (m, 4H), 2.77-2.65 (m, 6H), 2.23 (s, 3H), 2.04-1.94 (m, 1H), 1.59 (d, J=32.5 Hz, 2H), 1.50-1.02 (m, 9H).

Example 42: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting isomer (11 mg) from the separation of isomers by chiral SFC described in Example 41 was designated (*R): MS: mass calcd. for C₃₄H₃₉N₅O₆S, 645.3; m/z found, 646.2. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.44 (m, 1H), 8.23-8.15 (m, 1H), 7.95-7.78 (m, 1H), 7.26-6.90 (m, 5H), 4.98-4.81 (m, 1H), 4.60-4.33 (m, 2H), 4.09-3.89 (m, 2H), 3.77-3.28 (m, 4H), 2.88-2.53 (m, 6H), 2.23 (s, 3H), 2.06-1.93 (m, 1H), 1.69-1.51 (m, 2H), 1.49-0.95 (m, 9H).

Example 43: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid

Step A: Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(541′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate. A solution of methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate (Intermediate 56, 0.68 g, 1.7 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 0.68 g, 2.5 mmol), and triphenylphosphine (0.70 g, 2.7 mmol) in THF (16 mL) and DMF (12 ml) was stirred at room temperature for 5 minutes. DBAD (0.61 g, 2.7 mmol) was added and the reaction mixture was stirred for 30 minutes. The mixture was then concentrated under a stream of nitrogen and purified by flash column chromatography (0-100% EtOAc/hexanes, gradient elution) to afford the title compound (1.1 g, 91%). MS (ESI): mass calcd. for C₃₄H₄₀N₆O₆S, 660.3; m/z found, 661.3 [M+H]⁺.

Step B: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid. 2 M Aqueous lithium hydroxide (2.6 mL, 5.2 mmol) was added to a solution of methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate (350 mg, 0.53 mmol) in MeOH (3 mL). The reaction mixture was stirred at 75° C. overnight and then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was approximately 6. DCM was then added and the resulting biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, concentrated to dryness under reduced pressure and purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). The fractions that contained product from such preparative acidic HPLC were collected and lyophilized to dryness to provide the title compound (241 mg). MS (ESI): mass calcd. for C₃₃H₃₈N₆O₆S, 646.2; m/z found, 647.2 [M+H]⁺.

Example 44: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid (Example 43) was separated by chiral SFC (Chiralcel OJ-H, 2×25 cm, mobile phase: 80% CO₂, 20% MeOH with 0.1% diethylamine) to afford two enantiomers. The first eluting isomer (47 mg) was designated (*S): MS: mass calcd. for C₃₃H₃₈N₆O₆S, 646.2; m/z found, 647.2. ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.43 (m, 2H), 8.23-8.15 (m, 1H), 7.61 (s, 2H), 7.47 (s, 1H), 7.26-7.21 (m, 1H), 5.06-4.94 (m, 1H), 4.62-4.46 (m, 1H), 4.44-4.29 (m, 1H), 4.08-3.90 (m, 2H), 3.69-3.37 (m, 6H), 2.95-2.79 (m, 4H), 2.79-2.67 (m, 1H), 2.44 (s, 3H), 1.61-1.26 (m, 11H).

Example 45: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid

The second eluting isomer (54 mg) from the separation of isomers by chiral SFC described in Example 44 was designated (*R): MS: mass calcd. for C₃₃H₃₈N₆O₆S, 646.2; m/z found, 647.3. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=4.5 Hz, 2H), 8.24-8.15 (m, 1H), 7.70-7.53 (m, 2H), 7.50-7.41 (m, 1H), 7.28-7.22 (m, 1H), 5.06-4.92 (m, 1H), 4.65-4.48 (m, 1H), 4.42-4.26 (m, 1H), 4.14-3.90 (m, 2H), 3.67-3.37 (m, 6H), 2.93-2.36 (m, 8H), 1.63-1.26 (m, 11H).

Example 46: 2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a 100 mL round bottom flask under N₂ was added methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 48, 630 mg, 1.45 mmol), 7′-chloro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 68, 618 mg, 2.01 mmol), triphenylphosphine (561 mg, 2.14 mmol), tetrahydrofuran (7.5 mL) and DMF (7.5 mL). Once the mixture was homogeneous, diisopropyl azodicarboxylate (0.48 mL, 2.4 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. These extractions resulted in several organic fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:1 ethyl acetate/DCM) to afford the title compound (760 mg, 73%). MS (ESI): mass calcd. for C₃₃H₃₅ClF₃N₅O₆S, 721.2; m/z found, 722.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 7.13 (d, J=7.3 Hz, 1H), 7.05-7.03 (m, 2H), 4.72 (s, 1H), 4.47-4.33 (m, 2H), 3.98-3.91 (m, 2H), 3.58-3.47 (m, 6H), 3.37-3.33 (m, 1H), 2.71 (s, 3H), 2.16 (s, 3H), 1.70-1.56 (m, 2H), 1.49-1.39 (m, 2H), 1.35 (s, 3H), 1.29 (s, 3H).

Step B: Methyl 2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a reaction vessel under N₂ was added methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (200 mg, 0.28 mmol), 2-morpholinoethan-1-ol (101 μL, 0.83 mmol), Cs₂CO₃ (271 mg, 0.83 mmol) and toluene (2.0 mL, which had been previously purged with N₂ for 30 minutes). RockPhos Pd G3 (11.6 mg, 0.014 mmol) was then added to this mixture and the reaction mixture was purged with N₂ for an additional 5 minutes. The reaction mixture was then heated to 90° C. for 18 hours. Afterwards, the reaction was cooled, partitioned between ethyl acetate and water and the aqueous layer extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:10 MeOH/DCM) to afford the title compound (75 mg, 33%) as a white solid. MS (ESI): mass calcd. for C₃₉H₄₇F₃N₆O₈S, 816.3; m/z found, 817.2 [M+H]⁺.

Step C: 2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. To a flask was added methyl 2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (190 mg, 0.23 mmol), lithium hydroxide (2M, 0.8 mL, 1.6 mmol), MeOH (1.6 mL), THF (1.6 mL) and water (0.8 mL). The mixture was heated to 75° C. and stirred for 6 h. The reaction was cooled to room temperature, pH adjusted to about 4 with 2 M HCl, poured into water and extracted with ethyl acetate (4×). These extractions resulted in several organic solvent fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was purified by flash chromatography (eluent: 1:10 MeOH/DCM) to afford the title compound (40 mg, 21%). MS (ESI): mass calcd. for C₃₄H₄₅F₃N₆O₈S, 802.3; m/z found, 803.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.00-7.92 (m, 2H), 7.22-7.19 (m, 1H), 7.17-7.14 (m, 1H), 7.13-7.08 (m, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.81 (s, 1H), 4.50-4.30 (m, 4H), 3.93-3.83 (m, 2H), 3.69-3.52 (m, 7H), 3.40 (br s, 2H), 2.79-2.68 (m, 6H), 2.56-2.47 (m, 4H), 2.16 (s, 4H), 1.69-1.41 (m, 4H), 1.38 (s, 4H).

Example 47: (*S) 2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 2,2-dimethyl-3-(4-methyl-3-((7′-(2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid enantiomers (Example 46, 40 mg) was separated by chiral SFC (Stationary phase: Chiralpak IG, Sum, 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two enantiomers. The first eluting isomer (11 mg) was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₅F₃N₆O₈S, 802.3; m/z found, 803.1 [M+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=8.4 Hz, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.24-7.14 (m, 3H), 7.11-7.07 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 4.90 (s, 1H), 4.60-4.51 (m, 1H), 4.48-4.38 (m, 3H), 4.04-3.86 (m, 2H), 3.82-3.37 (m, 8H), 2.86 (s, 3H), 2.82-2.75 (m, 2H), 2.60-2.54 (m, 4H), 2.22 (s, 3H), 1.65-1.49 (m, 4H), 1.46 (s, 3H), 1.34 (s, 3H).

Example 48: (*R)-2,2-Dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The second eluting isomer (12 mg) from the separation of isomers by chiral SFC described in Example 47 was designated (*R): MS (ESI): mass calcd. for C₃₈H₄₅F₃N₆O₈S, 802.3; m/z found, 803.1 [M+H]⁺.

Example 49: 3-(3-((7′-(3-Hydroxyprop oxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (20 mg, 30%) was prepared using analogous conditions as described in Example 46 where 3-((2-(trimethylsilyl)propan-2-yl)oxy)propan-1-ol was used instead of 2-morpholinoethan-1-ol in step B. MS (ESI): mass calcd. for C₃₅H₄₀F₃N₆O₈S, 747.2; m/z found, 748.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=8.5 Hz, 1H), 7.94 (d, J=7.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.16-7.08 (m, 2H), 7.03 (d, J=7.9 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H), 4.83 (s, 1H), 4.50-4.32 (m, 4H), 3.93-3.79 (m, 2H), 3.73-3.67 (m, 3H), 3.62-3.35 (m, 3H), 2.78 (s, 3H), 2.16 (s, 3H), 1.94 (q, J=5.9 Hz, 3H), 1.60-1.52 (m, 3H), 1.45-1.37 (s, 4H), 1.28-1.20 (m, 4H).

Example 50: (*S) 3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methy-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-((7′-(3-hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid enantiomers (Example 49) was separated by chiral SFC (Stationary phase: Chiralpak AD-H, 5 μm, 250×30 mm, Mobile phase: 75% CO₂, 25% EtOH) to afford two enantiomers. The first eluting isomer (8 mg) was designated (*S): MS (ESI): mass calcd. for C₃₅H₄₀F₃N₆O₈S, 747.2; m/z found, 748.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.01-7.95 (m, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.18-7.11 (m, 2H), 7.09-6.98 (m, 2H), 6.56-6.52 (m, 1H), 4.82 (s, 1H), 4.48-4.34 (m, 4H), 3.94-3.83 (m, 2H), 3.75-3.55 (m, 4H), 3.37 (s, 3H), 2.75 (s, 3H), 2.16 (s, 3H), 2.04-1.93 (m, 2H), 1.61-1.45 (m, 3H), 1.37 (s, 4H), 1.27 (s, 3H).

Example 51: (*R) 3-(3-((7′-(3-Hydroxypropoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2′-dimethyl-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The second eluting isomer (9 mg) from the separation of isomers by chiral SFC described in Example 50 was designated (*R): MS (ESI): mass calcd. for C₃₅H₄₀F₃N₆O₈S, 747.2; m/z found, 748.1 [M+H]⁺.

Example 52: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

Step A: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate. A solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 49, 2.0 g, 4.8 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 1.6 g, 6.0 mmol), and triphenylphosphine (1.8 g, 7.1 mmol) in THF (133 mL) and DMF (13 ml) was stirred at room temperature for 5 minutes. DBAD (1.9 g, 7.9 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (3 g, 93% yield) which was carried on to the next step without further purification. MS (ESI): mass calcd. for C₃₃H₃₇F₂N₅O₆S, 669.2; m/z found, 670.3 [M+H]⁺.

Step B: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid. Lithium hydroxide (0.65 g, 15.5 mmol) was added to a solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (3.0 g, 3.9 mmol) in MeOH (25 mL) and water (17 mL). The reaction mixture was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was then added until the pH was 4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-10% MeOH/DCM, gradient elution) to provide the title compound (2.5 g, 98% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₂N₅O₆S, 655.2; m/z found, 656.3 [M+H]⁺.

Example 53: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid isomers (Example 52, 2.5 g) was separated by chiral SFC (stationary phase: Chiralpak IC, 30×150 mm, Mobile phase: 35% ethanol, 65% CO₂) to afford two enantiomers. The first eluting isomer (1.2 g) was designated (*S): ¹H NMR (500 MHz, CDCl₃) δ 8.52-8.45 (m, 1H), 8.23-8.18 (m, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.33-7.15 (m, 5H), 7.12-7.06 (m, 1H), 4.86 (s, 1H), 4.54-4.43 (m, 2H), 4.03-3.88 (m, 2H), 3.73-3.36 (m, 4H), 2.74 (s, 3H), 2.21 (s, 3H), 1.64-1.47 (m, 3H), 1.47-1.30 (m, 7H).

Example 54: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting isomer (1.1 g) from the separation of isomers by chiral SFC described in Example 53 was designated (*R): ¹H NMR (600 MHz, CDCl₃) δ 8.51-8.46 (m, 1H), 8.23-8.19 (m, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.29-7.07 (m, 6H), 4.86 (s, 1H), 4.57-4.50 (m, 1H), 4.48-4.40 (m, 1H), 4.06-3.92 (m, 2H), 3.68-3.57 (m, 2H), 3.57-3.36 (m, 2H), 2.75 (s, 3H), 2.23 (s, 3H), 1.63-1.32 (m, 10H).

Example 55: (R/S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Methyl 3-(4-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of methyl 3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 50, 480 mg, 1.1 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 420 mg, 1.55 mmol), DBAD (372 mg, 1.62 mmol) and triphenylphosphine (420 mg, 1.60 mmol) in THF (7.2 mL) and DMF (7.2 ml) was stirred at room temperature for 16 hours. The reaction was then concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (650 mg, 86% yield) which was taken on to the next step without further purification. MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.2 [M+H]⁺.

Step B: (R/S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Lithium hydroxide (166 mg, 6.92 mmol) was added to a solution of methyl 3-(4-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (650 mg, 0.94 mmol) in MeOH (43 mL) and water (13 mL). The reaction mixture was stirred at 70° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. EtOAc was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-10% MeOH/DCM, gradient elution) to provide the title compound to provide the title compound (188 mg, 30% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 674.2; m/z found, 675.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.55-8.51 (m, 1H), 8.40 (s, 1H), 8.16-8.12 (m, 1H), 7.97-7.93 (m, 1H), 7.38-7.32 (m, 2H), 7.31-7.25 (m, 1H), 4.81 (s, 1H), 4.59-4.51 (m, 1H), 4.42-4.34 (m, 1H), 4.10-3.99 (m, 2H), 3.79-3.53 (m, 4H), 2.96 (s, 3H), 2.26 (s, 3H), 1.76-1.60 (m, 3H), 1.54-1.45 (m, 1H), 1.44-1.33 (m, 6H).

Example 56: (*S)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (R/S)-3-(4-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 55, 280 mg) was separated by chiral SFC (stationary phase: Chiralpak IC, 5 μm, 250×30 mm, mobile phase: 55% CO₂, 45% mixture of Et₀H/DCM, 90/10, v/v) to afford two enantiomers. The first eluting isomer (54 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 674.2; m/z found, 675.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.56-8.50 (m, 1H), 8.39 (s, 1H), 8.17-8.12 (m, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.38-7.32 (m, 2H), 7.29-7.27 (m, 1H), 4.78 (s, 1H), 4.61-4.54 (m, 1H), 4.35-4.28 (m, 1H), 4.12-3.99 (m, 2H), 3.74-3.52 (m, 4H), 2.99 (s, 3H), 2.25 (s, 3H), 1.75-1.60 (m, 3H), 1.47-1.34 (m, 7H).

Example 57: (*R)-3-(4-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (58 mg) from the separation of isomers by chiral SFC described in Example 56 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 674.2; m/z found, 675.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.55-8.50 (m, 1H), 8.39 (s, 1H), 8.17-8.11 (m, 1H), 7.95-7.91 (m, 1H), 7.38-7.32 (m, 2H), 7.29-7.27 (m, 1H), 4.78 (s, 1H), 4.62-4.52 (m, 1H), 4.35-4.28 (m, 1H), 4.09-4.00 (m, 2H), 3.75-3.52 (m, 4H), 2.98 (s, 3H), 2.26 (s, 3H), 1.75-1.58 (m, 3H), 1.47-1.35 (m, 7H).

Example 58: (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

Step A: Methyl 3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. A solution of methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate (Intermediate 51, 1.5 g, 3.8 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 1.3 g, 4.7 mmol), triphenylphosphine (1.6 g, 6.0 mmol), and DBAD (1.4 g, 6.1 mmol) in THF (41 mL) and DMF (5 ml) was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (2.4 g, 98% yield) which was carried on to the next step without further purification. MS (ESI): mass calcd. for C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺.

Step B: (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid. Lithium hydroxide (0.44 g, 18.5 mmol) was added to a solution of methyl 3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (2.4 g, 3.7 mmol) in MeOH (30 mL), THF (60 mL) and water (30 mL). The reaction mixture was stirred at 70° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was approximately 3-4. EtOAc was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-10% MeOH/DCM, gradient elution) to provide the title compound (2.25 g, 96% yield). MS (ESI): mass calcd. for C₃₂H₃₈N₆O₆S, 634.3; m/z found, 635.3 [M+H]⁺.

Example 59: (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

The mixture of (R/S)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid isomers (Example 58, 2.25 g) was separated by chiral SFC (stationary phase: Chiralpak AD-H, 2×25 cm, Mobile phase: 65% CO₂, 35% EtOH) to afford two enantiomers. The first eluting isomer (1.01 g) was designated (*S): ¹H NMR (500 MHz, CDCl₃) δ 8.51-8.47 (m, 1H), 8.43-8.38 (m, 1H), 8.13-8.08 (m, 1H), 7.60-7.52 (m, 2H), 7.34-7.29 (m, 1H), 7.19-7.15 (m, 1H), 5.02 (s, 1H), 4.65-4.53 (m, 2H), 4.51-4.45 (m, 1H), 4.31-4.23 (m, 1H), 3.98-3.87 (m, 2H), 3.60-3.43 (m, 2H), 3.43-3.23 (m, 2H), 2.85 (s, 3H), 2.39 (s, 3H), 1.57-1.44 (m, 5H), 1.41-1.22 (m, 8H).

Example 60: (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

The second eluting isomer (1.04 g) from the separation of isomers by chiral SFC described in Example 59 was designated (*R): ¹H NMR (500 MHz, CDCl₃) δ 8.49-8.44 (m, 1H), 8.43-8.40 (m, 1H), 8.12-8.07 (m, 1H), 7.59-7.52 (m, 2H), 7.34-7.28 (m, 1H), 7.20-7.16 (m, 1H), 5.00 (s, 1H), 4.63-4.53 (m, 2H), 4.53-4.43 (m, 1H), 4.28-4.22 (m, 1H), 3.99-3.87 (m, 2H), 3.59-3.42 (m, 2H), 3.42-3.23 (m, 2H), 2.83 (s, 3H), 2.39 (s, 3H), 1.56-1.45 (m, 5H), 1.41-1.21 (m, 8H).

Example 61: (R/S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

Step A: Methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate (Intermediate 51, 1.5 g, 3.8 mmol), 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 1.3 g, 4.7 mmol), and triphenylphosphine (1.6 g, 6.0 mmol) in THF (41 mL) and DMF (5 ml) was stirred at room temperature for 5 minutes. DBAD (1.4 g, 6.1 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and purified by flash column chromatography (0-100% ethyl acetate/hexanes, gradient elution) to afford the title compound (2.5 g, 99% yield). MS (ESI): mass calcd. for C₃₄H₄₃N₆O₆S, 662.3; m/z found, 663.3 [M+H]⁺.

Step B: (R/S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid. Lithium hydroxide (0.45 g, 18.9 mmol) was added to a solution of methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (2.5 g, 3.8 mmol) in MeOH (30 mL), THF (60 mL) and water (30 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was approximately 6. DCM was then added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The product was purified by flash column chromatography (0-10% MeOH/DCM, gradient elution) to provide the title compound to provide the title compound (2.35 g, 96% yield). MS (ESI): mass calcd. for C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.52 (d, J=2.2 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.72-7.66 (m, 2H), 7.40 (d, J=8.7 Hz, 1H), 5.07 (s, 1H), 4.65 (qd, J=7.1, 3.5 Hz, 2H), 4.52 (d, J=15.5 Hz, 1H), 4.35 (d, J=15.6 Hz, 1H), 4.03-3.93 (m, 2H), 3.63-3.57 (m, 1H), 3.51 (dd, J=12.0, 4.4 Hz, 1H), 3.45 (s, 1H), 3.41-3.37 (m, 2H), 2.87 (s, 3H), 2.38 (s, 3H), 1.63-1.53 (m, 6H), 1.39-1.33 (m, 1H), 1.32 (s, 3H), 1.27 (dd, J=12.3, 4.3 Hz, 1H), 1.24 (s, 3H), 1.20-1.14 (m, 1H).

Example 62: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The mixture of (R/S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid isomers (Example 61, 2.35 g) was separated by chiral SFC (stationary phase: Chiralpak IC 5 μm 2×25 cm, Mobile phase: 60% CO₂, 40% MeOH) to afford two enantiomers. The first eluting isomer (1.1 g) was designated (*S): MS: mass calcd. C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.48 (d, J=2.2 Hz, 1H), 8.22-8.18 (m, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.60-7.53 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.02 (s, 1H), 4.58 (qd, J=7.0, 5.3 Hz, 2H), 4.46 (d, J=15.4 Hz, 1H), 4.26 (d, J=15.4 Hz, 1H), 3.91-3.83 (m, 2H), 3.56 (d, J=10.9 Hz, 1H), 3.43 (d, J=21.4 Hz, 1H), 3.33 (s, 2H), 2.85 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H), 1.56-1.44 (m, 4H), 1.39 (s, 4H), 1.27 (dd, J=12.3, 4.3 Hz, 1H), 1.24 (s, 3H), 1.20-1.14 (m, 1H).

Example 63: (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The second eluting isomer (1.1 g) from the separation of isomers by chiral SFC described in Example 62 was designated (*R): MS: mass calcd. C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.48 (d, J=2.2 Hz, 1H), 8.22-8.18 (m, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.60-7.53 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.02 (s, 1H), 4.58 (qd, J=7.0, 5.3 Hz, 2H), 4.46 (d, J=15.4 Hz, 1H), 4.26 (d, J=15.4 Hz, 1H), 3.91-3.83 (m, 2H), 3.56 (d, J=10.9 Hz, 1H), 3.43 (d, J=21.4 Hz, 1H), 3.33 (s, 2H), 2.85 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H), 1.56-1.44 (m, 4H), 1.39 (s, 4H), 1.27 (dd, J=12.3, 4.3 Hz, 1H), 1.24 (s, 3H), 1.20-1.14 (m, 1H).

Example 64: (*R)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

A solution of ethyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 27, 240 mg, 0.570 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-5 b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 137 mg, 0.570 mmol), and triphenylphosphine (131 mg, 0.570 mmol) in THF (10 mL) was stirred at room temperature for 5 minutes. DBAD (149 mg, 0.570 mmol) was added and the solution was stirred at room temperature for 2 hours. Saturated NaHCO₃(10 mL) was added and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated under reduced pressure. The resulting residue was dissolved in THF (2 mL) and NaOH (2M, 2 mL) was added to it. The mixture was stirred at room temperature for 24 hours. Water (5 mL) was then added, and the pH of the mixture was adjusted to about 3-4 by adding 1 M aqueous HCl solution. This solution was extracted with EtOAc (4 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂, gradient elution) to provide the title compound (180 mg, 51%). MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅O₅S, 615.2; m/z found, 616.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.30 (d, J=7.2 Hz, 1H), 8.25 (dd, J=2.4, 0.8 Hz, 1H), 8.14 (dd, J=2.4, 0.8 Hz, 1H), 7.22 (dd, J=7.9, 2.0 Hz, 1H), 7.16 (dd, J=7.7, 2.5 Hz, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.01-4.91 (m, 1H), 4.37-4.21 (m, 2H), 3.57-3.37 (m, 2H), 3.03-2.83 (m, 2H), 2.73 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H), 1.09-0.82 (m, 2H), 0.52-0.40 (m, 2H).

Example 65: 3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (240 mg, 82%) was prepared using analogous conditions as described in Example 11 where ethyl 3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Intermediate 58) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₂H₃₄F₂N₆O₄S, 636.2; m/z found, 637.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.27 (m, 1H), 8.09-8.05 (m, 1H), 8.03 (d, J=2.1 Hz, 1H), 7.90-7.76 (m, 1H), 7.58 (d, J=8.57 Hz, 1H), 7.36 (dd, J=8.7, 3.1 Hz, 1H), 7.25-7.17 (m, 1H), 7.18-7.09 (m, 1H), 6.83-6.76 (m, 1H), 5.40-5.34 (m, 1H), 4.65-4.37 (m, 4H), 4.10 (d, J=14.0 Hz, 1H), 3.65-3.56 (m, 2H), 3.37-2.97 (m, 3H), 2.94-2.76 (m, 1H), 2.28 (d, J=11.0 Hz, 3H), 2.09-1.44 (m, 3H), 1.26 (d, J=6.3 Hz, 2H), 0.70-0.59 (m, 2H), 0.53-0.41 (m, 2H).

Example 66: (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 65) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two diastereomers. The first eluting isomer (78 mg) was designated *S: MS (ESI): mass calcd. for C₃₂H₃₄F₂N₆O₄S, 636.2; m/z found, 637.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (dd, J=4.7, 1.8 Hz, 1H), 8.07 (dd, J=7.7, 1.8 Hz, 1H), 8.03-7.75 (m, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.24-7.09 (m, 3H), 6.80 (dd, J=7.7, 4.7 Hz, 1H), 5.36 (t, J=7.7 Hz, 1H), 4.59-4.37 (m, 4H), 4.10 (d, J=14.0 Hz, 1H), 3.65-3.54 (m, 2H), 3.22-3.15 (m, 2H), 3.07-2.96 (m, 1H), 2.90-2.73 (m, 1H), 2.29 (s, 3H), 1.99-1.85 (m, 1H), 1.77-1.52 (m, 2H), 1.42-1.20 (m, 2H), 0.68-0.62 (m, 2H), 0.53-0.43 (m, 2H).

Example 67: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,3′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (190 mg, 90% yield) was prepared using analogous conditions as described in Example 11 where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₁H₃₃N₅O₆S, 603.2; m/z found, 604.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56-8.55 (m, 1H), 8.27-8.24 (m, 1H), 7.46-7.38 (m, 2H), 7.36-7.34 (m, 1H), 7.23 (d, J=1.9 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.97 (dd, J=7.8, 1.9 Hz, 1H), 4.92-4.76 (m, 3H), 4.69 (d, J=13.7 Hz, 1H), 4.48 (d, J=7.1 Hz, 2H), 4.44-4.29 (m, 2H), 4.22-4.02 (m, 1H), 4.00-3.76 (m, 2H), 3.14-2.98 (m, 2H), 2.72 (s, 3H), 2.25 (s, 3H), 1.42-1.35 (m, 1H), 0.67-0.60 (m, 2H), 0.50-0.46 (m, 2H).

Example 68: (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-(difluoromethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 65) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two diastereomers. The second eluting isomer (72 mg) was designated *R: MS (ESI): mass calcd. for C₃₂H₃₄F₂N₆O₄S, 636.2; m/z found, 637.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (dd, J=4.7, 1.8 Hz, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H), 8.03-7.75 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.24-7.09 (m, 3H), 6.79 (dd, J=7.8, 4.8 Hz, 1H), 5.37 (t, J=7.7 Hz, 1H), 4.68-4.35 (m, 4H), 4.10 (d, J=14.2 Hz, 1H), 3.65-3.55 (m, 2H), 3.39-3.15 (m, 2H), 3.10-2.96 (m, 1H), 2.87 (t, J=12.7 Hz, 1H), 2.27 (s, 3H), 2.04-1.69 (m, 2H), 1.49 (dd, J=12.4, 6.5 Hz, 1H), 1.42-1.19 (m, 2H), 0.70-0.61 (m, 2H), 0.47 (dt, J=6.1, 4.9 Hz, 2H).

Example 69: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3 (3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,3′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 67) were separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two enantiomers. The first eluting isomer (63 mg) was designated *S: MS (ESI): mass calcd. for C₃₁H₃₃N₅O₆S, 603.2; m/z found, 604.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.56 (dd, J=4.9, 1.9 Hz, 1H), 8.26 (dd, J=7.6, 2.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.35 (dd, J=7.6, 4.9 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.97 (dd, J=7.8, 1.9 Hz, 1H), 4.91-4.80 (m, 3H), 4.71 (d, J=13.6 Hz, 1H), 4.48 (d, J=7.1 Hz, 2H), 4.42 (d, J=7.6 Hz, 1H), 4.34 (d, J=7.5 Hz, 1H), 4.16 (d, J=13.6 Hz, 1H), 3.98-3.91 (m, 1H), 3.84-3.78 (m, 1H), 3.14-2.99 (m, 2H), 2.72 (s, 3H), 2.26 (s, 3H), 1.43-1.33 (m, 1H), 0.69-0.60 (m, 2H), 0.54-0.45 (m, 2H).

Example 70: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(4-(difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 67) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two enantiomers. The second eluting isomer (70 mg) was designated *R: MS (ESI): mass calcd. for C₃₁H₃₃N₅O₆S, 603.2; m/z found, 604.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.56 (dd, J=4.9, 1.9 Hz, 1H), 8.26 (dd, J=7.6, 2.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.35 (dd, J=7.6, 4.9 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.97 (dd, J=7.8, 1.9 Hz, 1H), 4.91-4.80 (m, 3H), 4.71 (d, J=13.6 Hz, 1H), 4.48 (d, J=7.1 Hz, 2H), 4.42 (d, J=7.6 Hz, 1H), 4.34 (d, J=7.5 Hz, 1H), 4.16 (d, J=13.6 Hz, 1H), 3.98-3.91 (m, 1H), 3.84-3.78 (m, 1H), 3.14-2.99 (m, 2H), 2.72 (s, 3H), 2.26 (s, 3H), 1.43-1.33 (m, 1H), 0.69-0.60 (m, 2H), 0.54-0.45 (m, 2H).

Example 71: 3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (202 mg, 98% yield) was prepared using analogous conditions as described in Example 11 where ethyl 3-(4-difluoromethyl)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Intermediate 60) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39), in step B. MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₄S, 596.2; m/z found, 597.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.24 (m, 1H), 8.10-8.01 (m, 1H), 8.00-7.72 (m, 1H), 7.53 (dd, J=8.6, 1.3 Hz, 1H), 7.38 (dd, J=8.7, 1.4 Hz, 1H), 7.22-7.09 (m, 3H), 6.84-6.74 (m, 1H), 5.38-5.32 (m, 1H), 4.66-4.37 (m, 2H), 4.28 (d, J=3.1 Hz, 3H), 4.18-4.05 (m, 1H), 3.74-3.50 (m, 3H), 3.39-2.97 (m, 3H), 2.92-2.78 (m, 1H), 2.28 (d, J=10.3 Hz, 1H), 2.30-2.10 (m, 2H), 2.03-1.73 (m, 2H), 1.55-1.32 (m, 1H).

Example 72: (*S)-3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(4-(difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(34(R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 71) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The first eluting isomer (88 mg) was designated *S: MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₄S, 596.2; m/z found, 597.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.24 (m, 1H), 8.08-7.99 (m, 1H), 8.00-7.69 (m, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.15 (d, J=5.0 Hz, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.80-6.75 (m, 1H), 5.26 (t, J=7.6 Hz, 1H), 4.52-4.43 (m, 1H), 4.38 (d, J=14.0 Hz, 1H), 4.30-4.05 (s, 3H), 3.75-3.50 (m, 2H), 3.25-2.75 (m, 3H), 2.25 (s, 3H), 2.04-1.85 (m, 1H), 1.79-1.52 (m, 2H), 1.41-1.18 (m, 1H), 0.93 (s, 2H).

Example 73: (*R) 3-(4-(Difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(4-(difluoromethyl-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R-5,5-dioxido-7a,8,9,10-tetrahydropyridi[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 71) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The second eluting isomer (82 mg) was designated *R: MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₄S, 596.2; m/z found, 597.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.24 (m, 1H), 8.08-7.99 (m, 1H), 8.00-7.69 (m, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.15 (d, J=5.0 Hz, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.80-6.75 (m, 1H), 5.26 (t, J=7.6 Hz, 1H), 4.52-4.43 (m, 1H), 4.38 (d, J=14.0 Hz, 1H), 4.30-4.05 (s, 3H), 3.75-3.50 (m, 2H), 3.25-2.75 (m, 3H), 2.25 (s, 3H), 2.04-1.85 (m, 1H), 1.79-1.52 (m, 2H), 1.41-1.18 (m, 1H), 0.93 (s, 2H).

Example 74: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (360 mg, 93% yield) was prepared using analogous conditions as described in Example 11 where 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1′-dioxide (Intermediate 7) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₂H₃₄N₄O₆S, 602.2; m/z found, 603.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (dd, J=7.8, 1.7 Hz, 1H), 7.61-7.51 (m, 1H), 7.47-7.20 (m, 4H), 7.23-7.21 (m, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.93 (dd, J=7.8, 1.9 Hz, 1H), 5.00-4.82 (m, 1H), 4.76-4.69 (m, 3H), 4.48 (d, J=7.0 Hz, 2H), 4.41 (d, J=7.7 Hz, 1H), 4.37-4.26 (m, 1H), 4.10-3.70 (m, 3H), 3.14-2.96 (m, 2H), 2.71 (s, 3H), 2.27 (s, 3H), 1.46-1.34 (m, 1H), 0.70-0.59 (m, 2H), 0.53-0.44 (m, 2H).

Example 75: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The title compound (351 mg) was prepared using analogous conditions as described in Example 11 where 5′-methyl-2′,3′-dihydro-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepine] 1′,1′-dioxide (Intermediate 61) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.2; m/z found, 600.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.27-8.22 (m, 1H), 8.12-8.06 (m, 1H), 7.39-7.30 (m, 2H), 7.14 (d, J=1.6 Hz, 1H), 7.07 (s, 2H), 6.87 (dd, J=7.8, 4.7 Hz, 1H), 4.97 (t, J=7.8 Hz, 1H), 4.46 (d, J=7.0 Hz, 2H), 4.34 (s, 1H), 3.24-3.01 (m, 4H), 2.94 (s, 3H), 2.82 (s, 3H), 2.23 (s, 3H), 1.43-1.13 (m, 2H), 0.96-0.80 (m, 4H), 0.67-0.57 (m, 2H), 0.50-0.43 (m, 2H).

Example 76: (*R)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 74) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The second eluting isomer (145 mg) was designated *R: MS (ESI): mass calcd. for C₃₂H₃₄N₄O₆S, 602.2; m/z found, 603.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.53 (m, 1H), 7.45-7.35 (m, 3H), 7.34-7.28 (m, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.95 (dd, J=7.8, 1.9 Hz, 1H), 4.87 (dd, J=11.0, 5.2 Hz, 1H), 4.77-4.59 (m, 3H), 4.47 (d, J=7.0 Hz, 2H), 4.39 (d, J=7.6 Hz, 1H), 4.30 (d, J=7.4 Hz, 1H), 4.11 (d, J=13.7 Hz, 1H), 3.87-3.66 (m, 2H), 3.27-2.79 (m, 1H), 2.73 (s, 3H), 2.26 (s, 3H), 1.44-1.20 (m, 2H), 0.68-0.59 (m, 2H), 0.51-0.44 (m, 2H).

Example 77: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[benzo[b][1,4,5]oxathiazepin-4,3′-oxetan]-2,(3H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 74) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The first eluting isomer (137 mg) was designated *S: MS (ESI): mass calcd. for C₃₂H₃₄N₄O₆S, 602.2; m/z found, 603.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.53 (m, 1H), 7.45-7.35 (m, 3H), 7.34-7.28 (m, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.95 (dd, J=7.8, 1.9 Hz, 1H), 4.87 (dd, J=11.0, 5.2 Hz, 1H), 4.77-4.59 (m, 3H), 4.47 (d, J=7.0 Hz, 2H), 4.39 (d, J=7.6 Hz, 1H), 4.30 (d, J=7.4 Hz, 1H), 4.11 (d, J=13.7 Hz, 1H), 3.85 (d, J=15.4 Hz, 1H), 3.77-3.66 (m, 1H), 3.27-2.79 (m, 1H), 2.73 (s, 3H), 2.26 (s, 3H), 1.44-1.20 (m, 2H), 0.68-0.59 (m, 2H), 0.51-0.44 (m, 2H).

Example 78: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid (Example 75) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The first eluting isomer (116 mg) was designated *S: MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.2; m/z found, 600.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=4.8, 1.8 Hz, 1H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 7.38-7.29 (m, 2H), 7.13 (d, J=1.7 Hz, 1H), 7.07 (s, 2H), 6.90-6.84 (m, 1H), 4.97 (t, J=7.9 Hz, 1H), 4.45 (d, J=7.0 Hz, 2H), 4.34 (s, 2H), 3.23-3.02 (m, 4H), 2.95 (s, 3H), 2.83 (s, 3H), 2.23 (s, 3H), 1.44-1.20 (m, 1H), 0.95-0.79 (m, 4H), 0.68-0.58 (m, 2H), 0.52-0.41 (m, 2H).

Example 79: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid (Example 75) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The second eluting isomer (134 mg) was designated *R: MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.2; m/z found, 600.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=4.6, 1.8 Hz, 1H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 7.34 (d, J=2.0 Hz, 2H), 7.14 (s, 1H), 7.07 (s, 2H), 6.87 (dd, J=7.8, 4.7 Hz, 1H), 4.96 (t, J=7.7 Hz, 1H), 4.45 (d, J=7.0 Hz, 2H), 4.34 (s, 2H), 3.27-3.00 (m, 4H), 2.95 (s, 3H), 2.82 (s, 3H), 2.23 (s, 3H), 1.42-1.22 (m, 1H), 0.91-0.81 (m, 4H), 0.67-0.59 (m, 2H), 0.51-0.42 (m, 2H).

Example 80: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The title compound (260 mg, 88%) was prepared using analogous conditions as described in Example 11 where (*R)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 40) instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (dt, J=4.6, 2.2 Hz, 1H), 8.14 (ddd, J=7.7, 3.7, 1.9 Hz, 1H), 7.41-7.31 (m, 2H), 7.16 (d, J=13.7 Hz, 1H), 7.08 (dd, J=6.8, 1.2 Hz, 2H), 6.90 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 5.30 (s, 1H), 4.97 (td, J=7.9, 2.3 Hz, 1H), 4.72 (dd, J=14.9, 5.9 Hz, 1H), 4.45 (dd, J=7.1, 4.1 Hz, 2H), 4.27 (dd, J=14.9, 3.0 Hz, 1H), 3.95-3.79 (m, 1H), 3.58-3.43 (m, 2H), 3.25-3.03 (m, 2H), 2.87-2.68 (m, 4H), 2.26 (d, J=5.7 Hz, 3H), 1.89-1.57 (m, 4H), 1.42-1.12 (m, 1H), 0.75 (s, 1.5H), 0.69 (s, 1.5H), 0.67-0.57 (m, 2H), 0.46 (dtd, J=6.9, 4.8, 2.4 Hz, 2H).

Example 81: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid (Example 80) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The first eluting isomer (104 mg) was designated *R: MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (dd, J=4.8, 1.9 Hz, 1H), 8.14 (dd, J=7.7, 1.8 Hz, 1H), 7.43-7.32 (m, 2H), 7.16 (s, 1H), 7.08-7.05 (m, 2H), 6.91 (dd, J=7.7, 4.8 Hz, 1H), 4.96 (t, J=7.7 Hz, 1H), 4.73 (d, J=14.9 Hz, 1H), 4.45 (d, J=7.0 Hz, 2H), 4.26 (d, J=14.8 Hz, 1H), 3.92-3.83 (m, 1H), 3.64-3.27 (m, 2H), 3.20-3.03 (m, 2H), 2.86-2.70 (m, 4H), 2.26 (s, 3H), 1.82-1.70 (m, 1H), 1.68-1.61 (m, 2H), 1.40-1.31 (m, 1H), 0.89 (d, J=6.2 Hz, 1H), 0.76 (s, 3H), 0.68-0.57 (m, 2H), 0.54-0.40 (m, 2H).

Example 82: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid (Example 80) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The second eluting isomer (107 mg) was designated *S: MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (dd, J=4.8, 1.8 Hz, 1H), 8.12 (dd, J=7.7, 1.9 Hz, 1H), 7.42-7.29 (m, 2H), 7.19 (s, 1H), 7.08-7.02 (m, 2H), 6.90 (dd, J=7.7, 4.7 Hz, 1H), 4.96 (t, J=7.6 Hz, 1H), 4.72 (d, J=15.1 Hz, 1H), 4.44 (d, J=7.0 Hz, 2H), 4.25 (d, J=15.1 Hz, 1H), 3.97-3.84 (m, 1H), 3.77-3.63 (m, 2H), 3.56-3.50 (m, 1H), 3.45-2.93 (m, 2H), 2.85-2.78 (m, 4H), 2.24 (s, 3H), 1.90-1.62 (m, 2H), 1.41-1.18 (m, 1H), 0.92 (d, J=6.1 Hz, 1H), 0.70 (s, 3H), 0.66-0.56 (m, 2H), 0.52-0.40 (m, 2H).

Example 83: 3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a 20 mL vial under N₂ was added ethyl (E)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)acrylate (200 mg, 0.67 mmol, Intermediate 25, step A), (2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (288 mg, 1.07 mmol), potassium hydroxide (41 mg, 0.73 mmol), dioxane (3.0 mL), water (1.4 mL) and chloro(1,5-cyclooctadiene)rhodium(I) dimer (48 mg, 0.098 mmol). The vial was capped and stirred at r.t. for 18 h. The reaction was poured into aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 1:1 ethyl acetate/DCM) to afford the title compound (150 mg, 53%). MS (ESI): mass calcd. for C₂₀H₁₉ClF₃N₃O₃, 441.1; m/z found, 442.1 [M+H]⁺.

Step B: The title compound (153 mg, 89%) was prepared using analogous conditions as described in Example 11 where ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of ethyl 3-((1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and (*S)-7,7a,8,9,10-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₉H₂₈ClF₃N₆O₄S, 648.1; m/z found, 649.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.28 (m, 1H), 8.05-8.00 (m, 2H), 7.46-7.42 (m, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 7.08-7.02 (m, 1H), 6.89-6.79 (m, 2H), 4.95-4.88 (m, 1H), 4.62-4.43 (m, 3H), 4.33-4.23 (m, 1H), 3.54-3.34 (m, 2H), 3.31-2.94 (m, 5H), 1.81-1.70 (m, 3H), 1.65-1.50 (m, 3H), 1.33-1.16 (m, 1H).

Example 84: (*S)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 83) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% MeOH) to afford two enantiomers. The first eluting isomer (69 mg) was designated *S: MS (ESI): mass calcd. for C₂₉H₂₈ClF₃N₆O₄S, 648.1; m/z found, 649.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.28 (m, 1H), 8.05-8.00 (m, 2H), 7.44 (s, 1H), 7.30-7.25 (m, 1H), 7.05-7.02 (m, 1H), 6.89-6.79 (m, 2H), 4.93-4.86 (m, 1H), 4.62-4.43 (m, 3H), 4.33-4.23 (m, 1H), 3.54-3.34 (m, 2H), 3.31-2.75 (m, 5H), 1.81-1.69 (m, 3H), 1.65-1.50 (m, 3H), 1.33-1.16 (m, 1H).

Example 85: (*R)-3-(4-Chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 83) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% MeOH) to afford two enantiomers. The second eluting isomer (69 mg) was designated *R: MS (ESI): mass calcd. for C₂₉H₂₈ClF₃N₆O₄S, 648.1; m/z found, 649.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.28 (m, 1H), 8.05-8.00 (m, 2H), 7.44 (s, 1H), 7.30-7.25 (m, 1H), 7.05-7.02 (m, 1H), 6.92-6.79 (m, 2H), 4.93-4.86 (m, 1H), 4.62-4.43 (m, 3H), 4.33-4.23 (m, 1H), 3.54-3.34 (m, 2H), 3.31-2.75 (m, 5H), 1.81-1.69 (m, 3H), 1.65-1.50 (m, 3H), 1.33-1.16 (m, 1H).

Example 86: 3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (68 mg, 22%) was prepared using analogous conditions as described in Example 11 where ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 83, step A) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 2′3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₇H₂₃ClF₃N₅O₆S, 637.1; m/z found, 638.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J=4.9, 1.9 Hz, 1H), 8.21 (dd, J=7.7, 1.9 Hz, 1H), 8.05 (d, J=7.1 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.37-7.29 (m, 2H), 7.08 (dd, J=8.3, 2.2 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.9 Hz, 1H), 4.80-4.73 (m, 2H), 4.54 (d, J=3.3 Hz, 2H), 4.41-4.36 (m, 2H), 4.04-3.94 (m, 2H), 3.35-2.85 (m, 2H), 2.80 (s, 3H).

Example 87: (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 86) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% i-PrOH) to afford two enantiomers. The first eluting isomer (27 mg) was designated *R: MS (ESI): mass calcd. for C₂₇H₂₃ClF₃N₅O₆S, 637.1; m/z found, 638.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J=4.9, 1.9 Hz, 1H), 8.21 (dd, J=7.7, 1.9 Hz, 1H), 8.05 (d, J=7.1 Hz, 1H), 7.48 (s, 1H), 7.37-7.29 (m, 2H), 7.08 (dd, J=8.3, 2.2 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.9 Hz, 1H), 4.79-4.72 (m, 2H), 4.54 (d, J=3.3 Hz, 2H), 4.42-4.33 (m, 2H), 4.05-3.90 (m, 2H), 3.35-2.85 (m, 2H), 2.80 (s, 3H).

Example 88: (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-((1′,1′-dioxoidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 86) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% i-PrOH) to afford two enantiomers. The second eluting isomer (28 mg) was designated *S: MS (ESI): mass calcd. for C₂₇H₂₃ClF₃N₅O₆S, 637.1; m/z found, 638.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J=4.9, 1.9 Hz, 1H), 8.21 (dd, J=7.7, 1.9 Hz, 1H), 8.05 (d, J=7.1 Hz, 1H), 7.48 (s, 1H), 7.37-7.29 (m, 2H), 7.08 (dd, J=8.3, 2.2 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.9 Hz, 1H), 4.79-4.72 (m, 2H), 4.54 (d, J=3.3 Hz, 2H), 4.42-4.33 (m, 2H), 4.05-3.90 (m, 2H), 3.35-2.85 (m, 2H), 2.80 (s, 3H).

Example 89: 3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (51 mg, 31%) was prepared using analogous conditions as described in Example 11 where ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 83, step A) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and (*S)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 63) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₀H₃₀ClF₃N₆O₄S, 662.2; m/z found, 663.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.15-8.12 (m, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.87-7.84 (m, 1H), 7.46-7.42 (m, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 7.07-7.02 (m, 1H), 6.88 (dd, J=7.3, 4.2 Hz, 1H), 4.95-4.86 (m, 1H), 4.58-4.37 (m, 3H), 4.21-4.09 (m, 1H), 3.50-3.31 (m, 2H), 3.29-2.94 (m, 3H), 2.80 (m, 3H), 2.27 (s, 3H), 1.79-1.67 (m, 3H) 1.63-1.45 (m, 3H).

Example 90: (*R)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 89) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% i-PrOH) to afford two enantiomers. The first eluting isomer (27 mg) was designated *R: MS (ESI): mass calcd. for C₃₀H₃₀ClF₃N₆O₄S, 662.2; m/z found, 663.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=2.5 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.07 (dd, J=8.3, 2.3 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 4.97-4.90 (m, 1H), 4.55-4.36 (m, 3H), 4.20-4.13 (m, 1H), 3.50-3.30 (m, 2H), 3.26-3.18 (m, 1H), 3.11-2.96 (m, 2H), 2.80 (s, 3H), 2.27 (s, 3H), 1.79-1.45 (m, 6H).

Example 91: (*S)-3-(4-Chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 89) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% i-PrOH) to afford two enantiomers. The second eluting isomer (24 mg) was designated *S: MS (ESI): mass calcd. for C₃₀H₃₀ClF₃N₆O₄S, 662.2; m/z found, 663.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=2.5 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.07 (dd, J=8.3, 2.3 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 4.97-4.90 (m, 1H), 4.55-4.36 (m, 3H), 4.20-4.13 (m, 1H), 3.50-3.30 (m, 2H), 3.26-3.18 (m, 1H), 3.11-2.96 (m, 2H), 2.80 (s, 3H), 2.27 (s, 3H), 1.79-1.45 (m, 6H).

Example 92: 3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (125 mg, 65%) was prepared using analogous conditions as described in Example 11 where ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 83, step A) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and (*S)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 64) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₉H₂₇ClF₄N₆O₄S, 666.1; m/z found, 667.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=2.9 Hz, 1H), 8.06-8.01 (m, 1H), 7.80-7.76 (m, 1H), 7.45 (dd, J=7.8, 2.3 Hz, 1H), 7.31 (dd, J=8.2, 2.3 Hz, 1H), 7.10-7.02 (m, 1H), 6.92-6.84 (m, 1H), 5.02-4.88 (m, 1H), 4.56-4.38 (m, 3H), 4.25-4.40 (m, 1H), 3.52-2.97 (m, 5H), 2.81 (d, J=2.1 Hz, 3H), 1.80-1.70 (m, 3H), 1.68-1.47 (m, 3H).

Example 93: (*R)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 92) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% i-PrOH) to afford two diastereomers. The first eluting isomer (70 mg) was designated *R: MS (ESI): mass calcd. for C₂₉H₂₇ClF₄N₆O₄S, 666.1; m/z found, 667.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=3.0 Hz, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.78 (dd, J=7.4, 2.9 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 6.87 (d, J=7.3 Hz, 1H), 5.04-4.88 (m, 1H), 4.52-4.43 (m, 3H), 4.24-4.16 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.00 (m, 3H), 2.82 (s, 3H), 1.81-1.69 (m, 3H), 1.68-1.47 (m, 3H).

Example 94: (*S)-3-(4-Chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 92) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% i-PrOH) to afford two diastereomers. The second eluting isomer (55 mg) was designated *S: MS (ESI): mass calcd. for C₂₉H₂₇ClF₄N₆O₄S, 666.1; m/z found, 667.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=3.0 Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.79 (dd, J=7.4, 3.0 Hz, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.08 (dd, J=8.3, 2.3 Hz, 1H), 6.88 (d, J=7.3 Hz, 1H), 4.94 (dd, J=8.8, 6.8 Hz, 1H), 4.57-4.38 (m, 3H), 4.19 (dt, J=13.2, 4.7 Hz, 1H), 3.50-3.32 (m, 2H), 3.25 (ddd, J=13.7, 9.5, 4.7 Hz, 1H), 3.16-2.99 (m, 2H), 2.82 (s, 3H), 1.74 (dd, J=9.5, 4.2 Hz, 3H), 1.65-1.47 (m, 3H).

Example 95: 3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (120 mg, 84%) was prepared using analogous conditions as described in Example 11 where ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 83, step A) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₄H₂₄ClF₃N₄O₆S, 636.1; m/z found, 637.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=7.3 Hz, 1H), 7.84 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.37 (dd, J=8.1, 1.1 Hz, 1H), 7.34-7.28 (m, 2H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 4.93 (t, J=7.9 Hz, 1H), 4.70-4.64 (m, 2H), 4.58-4.40 (m, 2H), 4.37-4.33 (m, 2H), 3.95-3.81 (m, 2H), 3.18-2.96 (m, 2H), 2.78 (s, 3H).

Example 96: (*R)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 95) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% i-PrOH) to afford two enantiomers. The first eluting isomer (44 mg) was designated *R: MS (ESI): mass calcd. for C₂₄H₂₄ClF₃N₄O₆S, 636.1; m/z found, 637.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.1 Hz, 1H), 7.83 (dd, J=7.8, 1.7 Hz, 1H), 7.61-7.55 (m, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.38 (dd, J=8.1, 1.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.9 Hz, 1H), 4.70-4.63 (m, 2H), 4.54-4.34 (m, 4H), 3.95-3.82 (m, 2H), 3.16-2.93 (m, 2H), 2.79 (s, 3H).

Example 97: (*S)-3-(4-Chloro-3-((1′,1′-dioxoidospiro[benzo[b]]oxethiazepine-4,3′-oxetan]-2(3H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-chloro-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 95) isomers was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% i-PrOH) to afford two enantiomers. The second eluting isomer (40 mg) was designated *S: MS (ESI): mass calcd. for C₂₄H₂₄ClF₃N₄O₆S, 636.1; m/z found, 637.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.1 Hz, 1H), 7.83 (dd, J=7.8, 1.7 Hz, 1H), 7.60-7.55 (m, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.38 (dd, J=8.1, 1.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.06 (dd, J=8.3, 2.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.9 Hz, 1H), 4.70-4.63 (m, 2H), 4.54-4.34 (m, 4H), 3.95-3.82 (m, 2H), 3.16-2.93 (m, 2H), 2.79 (s, 3H).

Example 98: (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepin]-4,1′-cyclopropan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (531 mg, 89%) was prepared using analogous conditions as described in Example 11 where ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 26) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 8-fluoro-2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,1′-cyclopropane] 1,1-dioxide (Intermediate 65) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₉H₂₆F₄N₄O₅S, 618.2; m/z found, 619.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=7.1 Hz, 1H), 7.60 (dd, J=7.4, 3.1 Hz, 1H), 7.22-7.03 (m, 4H), 6.94 (dd, J=8.8, 4.3 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 4.26 (s, 2H), 3.22-2.97 (m, 2H), 2.79 (s, 3H), 2.28 (s, 3H), 1.05-0.98 (m, 2H), 0.51-0.41 (m, 2H).

Example 99: (*S)-3-(3-((8-Fluoro-1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl]-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)propanoic acid

The title compound (123 mg, 43%) was prepared using analogous conditions as described in Example 11 where ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 26) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 8-fluoro-2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 66) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₉H₂₆F₄N₄O₆S, 634.2; m/z found, 635.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=7.1 Hz, 1H), 7.60 (dd, J=7.3, 3.1 Hz, 1H), 7.36 (dd, J=8.8, 4.3 Hz, 1H), 7.30-7.23 (m, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.05-6.95 (m, 2H), 4.85 (dd, J=10.4, 5.9 Hz, 1H), 4.70 (dd, J=7.6, 5.0 Hz, 2H), 4.59 (d, J=13.9 Hz, 1H), 4.34-4.20 (m, 3H), 3.92-3.68 (m, 2H), 3.11-2.92 (m, 2H), 2.72 (m, 3H), 2.27 (s, 3H).

Example 100: (*S)-3-(3-((7′-Chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (212 mg, 76%) was prepared using analogous conditions as described in Example 11 where methyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 26) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 7′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyridio[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 67) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-[1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₂₄H₂₅ClF₃N₅O₅S, 635.1; m/z found, 636.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=8.1 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.04 (dd, J=7.8, 1.9 Hz, 1H), 6.87 (d, J=7.3 Hz, 1H), 4.93 (t, J=7.8 Hz, 1H), 4.34 (s, 2H), 3.59-3.49 (m, 2H), 3.01 (dd, J=16.1, 7.3 Hz, 2H), 2.80 (s, 3H), 2.27 (s, 3H), 1.26-1.19 (m, 2H), 0.68-0.59 (m, 2H).

Example 101: (*S)-3-(3-((7′-((2-Hydroxyethyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic acid

A vial was charged with (*S)-3-(3-((7′-chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (50 mg, 0.079 mmol, Example 100), 2-aminoethan-1-ol (29 mg, 0.47 mmol) and DMSO (0.5 mL). The vial heated to 130° C. for 1.5 h in a microwave reactor. The reaction was cooled, diluted with 1.0 mL of methanol and purified by reverse phase HPLC (5-70% MeCN-water with 20 mM NH₄OH) to afford the title compound as a white powder (23 mg, 44%) after lyophilization. MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₆S, 660.2; m/z found, 661.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=7.3 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.15 (dd, J=7.8, 1.9 Hz, 1H), 7.11-6.99 (m, 3H), 6.34 (d, J=8.6 Hz, 1H), 4.73 (t, J=7.7 Hz, 1H), 4.03 (q, J=14.4 Hz, 2H), 3.44 (t, J=5.9 Hz, 2H), 3.35-3.18 (m, 5H), 2.98 (dd, J=7.8, 3.0 Hz, 2H), 2.64 (s, 3H), 2.16 (s, 3H), 0.85 (s, 2H), 0.44 (s, 2H).

Example 102: (*S)-3-(3-((7′-((2-Hydroxypropyl)amino-1′,1′-dioxidospiro[cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridinn-7-yl)propanoic acid

The title compound (11 mg, 21%) was prepared using analogous conditions as described in Example 101 where 3-aminopropan-1-ol was used instead of 2-aminoethan-1-ol. MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J=7.3 Hz, 1H) 8.01 (d, J=7.2 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.12-7.10 (m, 2H), 7.07-7.04 (m, 1H), 6.90 (d, J=7.2 Hz, 1H), 6.27 (d, J=8.7 Hz, 1H), 5.96 (s, 1H), 4.92 (t, J=7.8 Hz, 1H), 4.28 (s, 2H), 3.67 (t, J=5.6 Hz, 2H), 3.50-3.46 (m, 4H), 3.09 (dd, J=15.9, 6.9 Hz, 1H), 2.96 (dd, J=15.8, 8.6 Hz, 1H), 2.82 (s, 3H), 2.30 (s, 3H), 1.84-1.73 (m, 2H), 1.22-1.16 (m, 2H), 0.53 (s, 2H).

Example 103: (*S)-3-(3-((7′-Hydroxy-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

A vial was charged with (*S)-3-(3-((7′-chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (50 mg, 0.079 mmol, Example 100), ethane-1,2-diol (29 mg, 0.47 mmol), cesium carbonate (38 mg, 0.12 mmol) and DMSO (0.5 ml). The vial heated to 130° C. for 1.5 h in a microwave reactor. The reaction was cooled, diluted with 1.0 mL of methanol and purified by reverse phase HPLC (eluent: MeCN/water with 20 mM NH₄OH, 5:95 to 70:30, gradient) to afford the title compound (8.5 mg, 18%) after lyophilization. MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.1; m/z found, 618.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=7.3 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.16-7.10 (m, 2H), 7.05 (dd, J=7.8, 2.0 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H), 6.46 (d, J=9.1 Hz, 1H), 4.93 (t, J=7.8 Hz, 1H), 4.33 (s, 2H), 3.53-3.45 (m, 2H), 3.47-3.38 (m, 1H), 3.11 (dd, J=15.9, 7.3 Hz, 1H), 2.97 (dd, J=15.9, 8.3 Hz, 1H), 2.81 (s, 3H), 2.30 (s, 3H), 1.35-1.25 (m, 2H), 0.68-0.61 (m, 2H).

Example 104: 3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: ethyl 3-(4-chloro-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The title compound (150 mg, 18%) was prepared using analogous conditions as described in example 11 where ethyl 3-(4-chloro-3-(hydroxymethyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 83, step A) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6) was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₃₀H₂₉ClF₃N₅O₅S, 663.1; m/z found, 664.0 [M+H]⁺.

Step B: ethyl 3-(4-cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo-4,3-a]pyridine-7-yl)propanoate. To a 9 mL screw capped pressure vessel under N₂ was added ethyl 3-(4-chloro-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (150 mg, 0.23 mmol), zinc cyanide (53 mg, 0.45 mmol), X-Phos (22 mg, 0.046 mmol), zinc powder (6 mg, 0.092 mmol), Pd₂(dba)₃ (21 mg, 0.023 mmol) and DMA (2.0 mL). N₂ was bubbled through this mixture for 20 min. and then heated to 110° C. for 72 h. The reaction was cooled, poured into saturated bicarbonate solution and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexanes, 0:1 to 30:10, gradient elution) to afford the title compound. MS (ESI): mass calcd. for C₃₁H₂₉F₃N₆O₅S, 654.2; m/z found, 665.0 [M+H]⁺.

Step C: 3-(4-cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (43 mg, 90%) was prepared using analogous conditions as described in example 11 where ethyl 3-(4-cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo-4,3-a]pyridine-7-yl)propanoate was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoate in Step C. MS (ESI): mass calcd. for C₂₉H₂₅F₃N₆O₅S, 626.2; m/z found, 627.0 [M+H]⁺.

Example 105: (*S)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 104) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 25*2 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The first eluting isomer (17.5 mg) was designated *S: MS (ESI): mass calcd. for C₂₉H₂₅F₃N₆O₅S, 626.2; m/z found, 627.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.09-8.00 (m, 2H), 7.74 (s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.97-6.86 (m, 1H), 5.04 (s, 1H), 4.50 (s, 2H), 3.90-3.50 (m, 2H), 3.23-2.97 (m, 2H), 2.82 (s, 3H), 2.43 (s, 3H), 1.30-1.19 (m, 2H), 0.80-0.72 (m, 2H).

Example 106: (*R)-3-(4-Cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(4-cyano-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]trizolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 104) was separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 25*2 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The second eluting isomer (10.4 mg) was designated *R: MS (ESI): mass calcd. for C₂₉H₂₅F₃N₆O₅S, 626.2; m/z found, 627.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.09-8.00 (m, 2H), 7.74 (s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.97-6.86 (m, 1H), 5.04 (s, 1H), 4.50 (s, 2H), 3.90-3.50 (m, 2H), 3.23-2.97 (m, 2H), 2.82 (s, 3H), 2.43 (s, 3H), 1.30-1.19 (m, 2H), 0.80-0.72 (m, 2H).

Example 107: (*S)-3-(3-((7′-((3-Methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: ethyl (*S)-3-(3-((7′-((3-methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. A vial was charged with ethyl (*S)-3-(3-((7′-chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (50 mg, 0.075 mmol, Example 100), 3-methoxypropan-1-amine (40 mg, 0.45 mmol) and DMSO (0.5 mL). The vial was capped then heated to 110° C. for 1 h in a microwave reactor. The reaction was cooled, poured into water and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexanes, 0:100 to 70:30, gradient elution) to afford the title compound (54 mg, 100%). MS (ESI): mass calcd. for C₃₄H₃₉F₃N₆O₆S, 716.3; m/z found, 717.2 [M+H]⁺.

Step B: (*S)-3-(3-((7′-(3-methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. To a 20 mL vial was added ethyl (*S)-3-(3-((7′-((3-methoxypropyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (54 mg, 0.075 mmol), THF (1.0 mL), 1M NaOH (1.0 mL) and ethanol (0.1 mL). This mixture was stirred at r.t. for 6 h followed by adjustment of the pH to between 3-5. The reaction was then poured into water and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (49 mg, 94%). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J=7.2 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.16-7.09 (m, 2H), 7.02 (dd, J=7.8, 2.0 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 6.23 (d, J=8.7 Hz, 1H), 4.95 (t, J=7.7 Hz, 1H), 4.33 (d, J=14.4 Hz, 1H), 4.24 (d, J=14.5 Hz, 1H), 3.48 (t, J=5.7 Hz, 3H), 3.34 (s, 4H), 3.16 (dd, J=15.9, 7.0 Hz, 1H), 3.03 (dd, J=15.9, 8.6 Hz, 1H), 2.84 (s, 3H), 2.30 (s, 3H), 1.91-1.84 (m, 2H), 1.30-1.23 (m, 3H), 1.10-1.05 (m, 1H), 1.02-0.93 (m, 1H), 0.50-0.44 (m, 1H), 0.42-0.37 (m, 1H).

Example 108: (*S)-3-(−3-((7′-(3-Hydroxypropyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (44 mg, 86%) was prepared using analogous conditions as described in Example 107 where 3-(methylamino)propan-1-ol was used instead of 3-methoxypropan-1-amine in Step A. MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=7.2 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.00 (dd, J=7.8, 2.0 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H), 6.35 (d, J=8.8 Hz, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.31 (s, 2H), 3.71-3.66 (m, 2H), 3.55-3.38 (m, 4H), 3.16 (dd, J=16.0, 7.4 Hz, 1H), 3.06-2.95 (m, 4H), 2.82 (s, 3H), 2.30 (s, 3H) 1.82-1.72 (m, 2H), 1.30-1.24 (m, 2H), 1.16-1.10 (m, 2H), 0.57-0.48 (m, 2H).

Example 109: (*S)-3-(−3-((7′-((3-Methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: ethyl (*S)-3-(−3-((7′-((3-methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a 9 mL screw cap pressure vial under nitrogen was added (*S)-3-(−34(7′-chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (100 mg, 0.15 mmol, Example 100), propane-1,3-diol (27 mg, 0.3 mmol), cesium carbonate (103 mg, 0.32 mmol), RockPhos Pd G3 (6.3 mg, 0.007 mmol) and toluene (1.0 mL). Nitrogen was bubbled through the reaction mixture for 10 min, and then heated to 90° C. for 18 h. The reaction was cooled, partitioned between ethyl acetate/water and the aqueous layer extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexanes, 0:100 to 70:30, gradient elution) to afford the title compound (30 mg, 28%). MS (ESI): mass calcd. for C₃₄H₃₈F₃N₅O₇S, 717.2; m/z found, 718.2 [M+H]⁺.

Step B: (*S)-3-(−3-((7′-(3-methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic acid. To a 20 mL scintillation vial was added ethyl (*S)-3-(−3-((7′-((3-methoxypropoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (30 mg, 0.042 mmol), THF (0.6 mL), 1M NaOH (0.6 mL) and ethanol (0.06 mL). This mixture was stirred at r.t. for 18 h followed by adjustment of the pH to between 3-5. The reaction was then poured into water and extracted with ethyl acetate (4×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (38 mg). MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₇S, 689.2; m/z found, 690.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=8.4 Hz, 1H), 7.96-7.91 (m, 1H), 7.25-7.21 (m, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.86 (s, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.53 (t, J=6.1 Hz, 2H), 3.34 (s, 3H), 3.02-2.92 (m, 1H), 2.88-2.73 (m, 1H), 2.72 (s, 3H), 2.33-2.28 (m, 1H), 2.20 (s, 3H), 2.08-1.95 (m, 2H), 1.71-1.58 (m, 1H), 1.45-1.10 (m, 2H), 0.97-0.75 (m, 2H), 0.57 (br s, 2H).

Example 110: (*S)-3-(−3-((7′4(3-Hydroxyethyl)(methyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (36 mg, 97%) was prepared using analogous conditions as described in Example 107 where 2-(methylamino)ethyan-1-ol was used instead of 3-methoxypropan-1-amine in Step A. MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J=7.2 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.02 (dd, J=7.9, 2.0 Hz, 1H), 6.89 (d, J=7.3 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 4.92 (t, J=7.8 Hz, 1H), 4.28 (s, 2H), 3.87-3.83 (m, 2H), 3.76-3.71 (m, 2H), 3.46 (s, 2H), 3.18-3.12 (m, 4H), 3.00 (dd, J=16.1, 8.4 Hz, 1H), 2.79 (s, 3H), 2.28 (s, 3H), 1.13-1.07 (m, 2H), 0.54-0.45 (m, 2H).

Example 111: (*S)-3-(4-Methyl-((7′-((2-morpholinoethyl)amino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (69 mg, 93%) was prepared using analogous conditions as described in Example 107 where 2-morpholinoethan-1-amine was used instead of 3-methoxypropan-1-amine in Step A. MS (ESI): mass calcd. for C₃₄H₃₈F₃N₇O₆S, 729.2; m/z found, 730.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=7.1 Hz, 1H), 7.75-7.67 (m, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.09-7.05 (m, 1H), 6.90 (d, J=7.3 Hz, 1H), 6.62-6.50 (m, 1H), 6.00-5.90 (m, 1H), 4.94 (t, J=7.8 Hz, 1H), 4.29 (s, 2H), 3.75-3.70 (m, 4H), 3.52-3.37 (m, 4H), 3.12 (dd, J=15.9, 8.2 Hz, 1H), 2.92 (dd, J=15.9, 7.4 Hz, 1H), 2.83-2.60 (m, 9H), 2.28 (s, 3H), 1.13-1.07 (m, 2H), 0.49-0.43 (m, 2H).

Example 112: (*S)-3-(3-((1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethyl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (65 mg, 84%) was prepared using analogous conditions as described in Example 107 where 2-(piperidin-1-yl)ethan-1-amine was used instead of 3-methoxypropan-1-amine in Step A. MS (ESI): mass calcd. for C₃₅H₄₀F₃N₇O₅S, 727.2; m/z found, 728.2 [M+H]⁺. ¹H NMR (600 MHz, Methanol-d₄) δ 8.31 (d, J=7.2 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.24 (dd, J=7.9, 2.0 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 6.46 (d, J=8.6 Hz, 1H), 4.97 (t, J=7.8 Hz, 1H), 4.32 (d, J=14.4 Hz, 1H), 4.22 (d, J=14.5 Hz, 1H), 3.74 (t, J=5.9 Hz, 2H), 3.55-3.49 (m, 1H), 3.35-3.23 (m, 4H), 3.14 (dd, J=15.8, 7.1 Hz, 1H), 3.07-2.96 (m, 1H), 2.77 (s, 3H), 2.31 (s, 3H), 1.90-1.82 (m, 4H), 1.74-1.65 (m, 2H), 1.42-1.27 (m, 2H), 1.03-0.88 (m, 4H), 0.52-0.40 (m, 2H).

Example 113: (*S)-3-(3-((7′-(Butylamino)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (35 mg, 91%) was prepared using analogous conditions as described in Example 107 where butan-1-amine was used instead of 3-methoxypropan-1-amine in Step A. MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₅S, 672.2; m/z found, 673.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=7.1 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.08-7.02 (m, 2H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.14 (d, J=8.7 Hz, 1H), 4.89 (t, J=7.7 Hz, 1H), 4.26 (d, J=14.4 Hz, 1H), 4.16 (d, J=14.4 Hz, 1H), 3.43 (d, J=15.4 Hz, 1H), 3.28 (d, J=15.4 Hz, 1H), 3.19-3.06 (m, 3H), 2.97 (dd, J=15.9, 8.5 Hz, 1H), 2.78 (s, 3H), 2.24 (s, 3H), 1.58-1.47 (m, 2H), 1.39-1.27 (m, 2H), 1.26-1.15 (m, 1H), 1.02-0.95 (m, 1H), 0.90-0.82 (m, 4H), 0.48-0.28 (m, 2H).

Example 114: 3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Methyl-3-(3-((7′-((3-hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The title compound (133 mg, 100%) was prepared using analogous conditions as described in Example 107 where 3-aminopropan-1-ol was used instead of 3-methoxypropan-1-amine and methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazoo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69) instead of ethyl (*S)-3-(3-((7′-chloro-1′,1′-dioxidospiro(cyclopropane-1.4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 100) in Step A. MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.3 [M+H]⁺.

Step B: 3-(3-((7′-((3-hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. In a 20 mL scintillation vial was added Methyl-3-(3-((7′-((3-hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (133 mg, 0.18 mmol), LiOH (2.0M solution in water, 0.6 mL, 1.2 mmol), MeOH (1.2 mL) and water (0.6 mL). The reaction was heated to 75 C for 6 h, followed by cooling to room temperature and pH adjustment to 4 with 2M HCl. The mixture was then further diluted with water and extracted with ethyl acetate (4×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (100 mg, 77%). MS (ESI): mass calcd. for C₃₅H₄₁F₃N₆O₇S, 746.3; m/z found, 747.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=7.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.22-7.15 (m, 2H), 7.08-7.00 (m, 2H), 6.14 (d, J=8.6 Hz, 1H), 5.51 (br s, 1H), 4.82 (s, 1H), 4.47-4.31 (m, 2H), 3.90-3.80 (m, 2H), 3.71-3.24 (m, 8H), 2.74 (s, 3H), 2.18 (s, 3H), 1.79-1.41 (m, 5H), 1.37 (s, 3H), 1.32-1.25 (m, 4H), 1.22-1.17 (m, 1H).

Example 115: (*S)-3-(3-((7′-(3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-0)propanoic acid

The mixture of 3-(3-((7′-((3-hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 114) were separated by chiral SFC (Chiralpak IC 5 μM, 250×21.2 mm, 65% CO₂, 35% MeOH). The first eluting isomer (14 mg) was designated *S: MS (ESI): mass calcd. for C₃₅H₄₁F₃N₆O₇S, 746.3; m/z found, 747.5 [M+H]⁺.

Example 116: (*R)-3-(3-((7′-((3-Hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-((7′-((3-hydroxypropyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 115) were separated by chiral SFC (Chiralpak IC 5 μM, 250×21.2 mm, 65% CO₂, 35% MeOH). The second eluting isomer (19 mg) was designated *R: MS (ESI): mass calcd. for C₃₅H₄₁F₃N₆O₇S, 746.3; m/z found, 747.0 [M+H]⁺.

Example 117: 3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (110 mg, 86%) was prepared using analogous conditions as described in Example 114 where (R)-3-aminobutan-1-ol was used instead of 3-aminopropan-1-ol and in Step A. MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.94 (dd, J=7.3, 2.5 Hz, 1H), 7.74 (dd, J=8.5, 1.5 Hz, 1H), 7.23-7.16 (m, 1.5H), 7.13 (d, J=2.1 Hz, 0.5H), 7.08 (dd, J=7.9, 2.0 Hz, 0.5H), 7.05-6.95 (m, 1.5H), 6.15 (dd, J=11.4, 8.5 Hz, 1H), 4.98 (br s, 1H), 4.82 (d, J=16.1 Hz, 1H), 4.44-4.30 (m, 2H), 4.07 (br s, 1H), 3.90-3.76 (m, 2H), 3.69-3.38 (m, 5H), 3.12 (s, 1H), 2.74 (d, J=6.6 Hz, 3H), 2.19 (d, J=2.1 Hz, 3H), 1.87 (br s, 1H), 1.74-1.38 (m, 4H), 1.37-1.33 (m, 3H), 1.30-1.10 (m, 8H).

Example 118: 3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (110 mg, 86%) was prepared using analogous conditions as described in Example 114 where (S)-3-aminobutan-1-ol was used instead of 3-aminopropan-1-ol in Step A. MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.95 (dd, J=7.3, 2.1 Hz, 1H), 7.74 (dd, J=8.6, 1.4 Hz, 1H), 7.22-7.16 (m, 1.5H), 7.13 (d, J=2.2 Hz, 0.5H), 7.08 (dd, J=8.0, 2.0 Hz, 0.5H), 7.06-6.98 (m, 1.5H), 6.15 (dd, J=10.9, 8.6 Hz, 1H), 5.00 (br s, 1H), 4.82 (d, J=15.1 Hz, 1H), 4.45-4.31 (m, 2H), 4.12-4.00 (m, 1H), 3.91-3.77 (m, 2H), 3.68-3.39 (m, 5H), 3.16 (br s, 1H), 2.74 (d, J=6.4 Hz, 3H), 2.19 (d, J=1.9 Hz, 3H), 1.87 (br s, 1H), 1.73-1.41 (m, 4H), 1.36 (d, J=5.0 Hz, 3H), 1.30-1.13 (m, 8H).

Example 119: (*S)-3-(3-((7′4(R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-((7′-(((R)-4-hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 117) were separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 25*2 mm, Mobile phase: 60% CO₂, 40% EtOH). The first eluting isomer (31 mg) was designated *S: MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.2 [M+H]⁺.

Example 120: (*R)-3-(3-((7′-(((R)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-((7′-(((R)-4-hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 117) were separated by chiral SFC (Stationary phase:

Chiralpak AD-H 5 μm 25*2 mm, Mobile phase: 60% CO₂, 40% EtOH). The second eluting isomer (31 mg) was designated *R: MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.2 [M+H]⁺.

Example 121: (*S)-3-(3-((7′ 4(S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4[triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-((7′-(((S)-4-hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 118) were separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 25*2 mm, Mobile phase: 60% CO₂, 40% EtOH). The first eluting isomer (36 mg) was designated *S: MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.2 [M+H]⁺.

Example 122: (*R)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-((7′-(((S)-4-hydroxybutan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 118) were separated by chiral SFC (Stationary phase: Chiralpak AD-H 5 μm 25*2 mm, Mobile phase: 60% CO₂, 40% EtOH). The second eluting isomer (31 mg) was designated *R: MS (ESI): mass calcd. for C₃₆H₄₃F₃N₆O₇S, 760.3; m/z found, 761.2 [M+H]⁺.

Example 123: (*R)-3-(3-((7′-(((S)-4-Hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (76 mg, 87%) was prepared using analogous conditions as described in example 114 where (S)-3-aminobutan-1-ol was used instead of 3-aminopropan-1-ol and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 36) in Step A. MS (ESI): mass calcd. for C₃₇H₄₅F₃N₆O₇S, 774.3; m/z found, 775.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J=7.4 Hz, 1H), 7.61 (s, 1H), 7.23-7.19 (m, 1H), 7.13-7.07 (m, 2H), 7.03 (d, J=8.3 Hz, 1H), 4.83 (s, 1H), 4.47-4.31 (m, 3H), 3.95-3.68 (m, 3H), 3.66-3.44 (m, 4H), 3.07 (d, J=15.4 Hz, 1H), 2.78 (s, 3H), 2.19 (s, 3H), 2.03 (d, J=0.8 Hz, 3H), 1.90-1.83 (m, 1H), 1.71-1.48 (m, 3H), 1.44-1.39 (m, 1H), 1.37 (s, 3H), 1.31-1.23 (m, 6H) 1.20-1.13 (m, 2H).

Example 124: (*R)-3-(3-((7′-(((R)-3-Hydroxy-3-methylbutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (113 mg, 69%) was prepared using analogous conditions as described in Example 114 where (R)-3-amino-2-methylbutan-2-ol was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 36). MS (ESI): mass calcd. for C₃₄H₄₇F₃N₆O₇S, 788.3; m/z found, 789.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H), 8.33 (d, J=7.2 Hz, 1H), 7.44 (s, 1H), 7.22-7.11 (m, 3H), 7.07 (d, J=7.9 Hz, 1H), 5.73 (d, J=8.9 Hz, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.31 (d, J=15.2 Hz, 1H), 4.20 (d, J=15.2 Hz, 1H), 4.10-4.04 (m, 1H), 3.79-3.58 (m, 2H), 3.35 (d, J=10.2 Hz, 1H), 3.28-3.15 (m, 2H), 2.58 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H), 1.42 (d, J=13.9 Hz, 2H), 1.30-1.13 (m, 9H), 1.10-0.97 (m, 9H).

Example 125: (*R)-3-(3-((7′-(((1s,3S)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (61 mg, 50%) was prepared using analogous conditions as described in Example 114 where (1s,3s)-3-aminocyclobutan-1-ol was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Example 36). MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S, 772.3; m/z found, 773.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=7.2 Hz, 1H), 7.48 (d, J=0.9 Hz, 1H), 7.32-7.22 (m, 2H), 7.17 (s, 1H), 7.12 (d, J=7.9 Hz, 1H), 6.77 (d, J=5.9 Hz, 1H), 5.00 (br s, 1H), 4.80 (s, 1H), 4.51-4.17 (m, 5H), 3.81-3.72 (m, 3H), 3.60-3.10 (m, 2H), 2.63 (s, 3H), 2.36-2.23 (m, 2H), 2.21-2.13 (m, 5H), 2.08 (s, 3H), 1.46 (d, J=14.0 Hz, 2H), 1.30-1.16 (m, 8H).

Example 126: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Benzyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethyoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]propanoate. The title compound (130 mg, 59%) was prepared using analogous conditions as described Example 11 where benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 17) was used instead of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-hydroxymethyl)-4-methylphenyl)propanoate (Example 11, step A) and 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3 [1,4,5]oxathiazepine]1′,1′-dioxide was used instead of (*S)-7a-methyl-6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) in step B. MS (ESI): mass calcd. for C₄₇H₅₅F₃N₆O₇S, 904.4; m/z found, 905.3 [M+H]⁺.

Step B: (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido3-(3-((7′-(((S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. Benzyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethyoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]propanoate (85 mg, 0.09 mmol) was dissolved in methanol (3.0 mL) and continuously flowed through a hydrogenation flow system fitted with a 20% Pd(OH)₂ on carbon cartridge at a flow rate of 1.0 mL/min. and a temperature of 50° C. for 20 minutes. The eluent from the hydrogenation flow system was collected in a 20 mL scintillation vial and solvent removed under reduced pressure. The residue was dried in a vacuum oven at 60° C. for 24 h giving the title compound (30 mg, 39%). MS (ESI): mass calcd. for C₄₀H₄₉F₃N₆O₇S, 814.3; m/z found, 815.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=7.2 Hz, 1H), 7.86 (s, 1H), 7.28-7.23 (m, 2H), 7.21 (s, 1H), 7.15 (d, J=7.9 Hz, 1H), 4.81 (s, 1H), 4.48-4.41 (m, 3H), 4.36-4.28 (m, 1H), 3.80-3.68 (m, 2H), 3.50-3.40 (m, 7H), 2.78-2.68 (m, 2H), 2.66 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 1.56-1.45 (m, 6H), 1.42-1.22 (m, 11H).

Example 127: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-3-(3-((7′-(((*S)-4-hydroxybutan-2-yl)amino)-8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (130 mg, 83%) was prepared using analogous conditions as described in Example 126 where 7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide in step A. MS (ESI): mass calcd. for C₃₉H₄₇F₃N₆O₇S, 800.3; m/z found, 801.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.98-7.93 (m, 2H), 7.27 (d, J=7.4 Hz, 1H), 7.12-7.05 (m, 2H), 7.02 (d, J=7.9 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 4.75 (s, 1H), 4.52-4.31 (m, 4H), 3.92-3.79 (m, 2H), 3.61-3.47 (m, 2H), 3.43-3.23 (m, 2H), 2.99-2.86 (m, 2H), 2.75-2.64 (m, 6H), 2.19 (s, 3H), 1.95 (s, 2H), 1.62-1.41 (m, 6H), 1.40-1.20 (m, 9H).

Example 128: (*R)-3-(3-((7′-(3-((2-Hydroxy ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: (*R)-3-(2′-(5-(3-methoxy-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]-triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid. methyl (*R)-3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]propanoate (100 mg, 0.12 mmol, Intermediate 74) was added to a 20 mL scintillation vial and dissolved in a 1:1 solution of DCM/TFA (1.0 mL). The mixture was stirred for 1 h then the solvent removed under reduced pressure. The resulting residue was dissolved in 1:1 DCM/MeCN and the solvent removed under reduced pressure. This process was repeated twice, and the final residue dried overnight at 60° C. in a vacuum oven producing the title compound (118 mg, 116% yield). MS (ESI): mass calcd. for C₃₆H₄₀F₃N₅O₈S, 760.2; m/z found, 761.2 [M+H]⁺.

Step B: methyl (*R)-3-(3-((7′-(3-((2-hydroxyethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a 15 mL round bottom flask under N₂ was added (*R)-3-(2′-(5-(3-methoxy-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid (118 mg, 0.16 mmol), DMF (2.0 mL), TEA (0.07 mL) and HATU (88 mg, 0.23 mmol). This mixture was stirred for 15 min. followed by addition of ethanolamine (28 mg, 0.46 mmol). The reaction was stirred for 24 h at r.t. then poured into saturated bicarbonate and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in DCM and purified by silica gel chromatography (eluent: MeOH/DCM, 0:100 to 10:90, gradient) to afford the title compound (60 mg, 48%). MS (ESI): mass calcd. for C₃₄H₄₅F₃N₆O₈S, 802.3; m/z found, 803.3 [M+H]⁺.

Step C: (*R)-3-(3-((7′-(3-((2-hydroxyethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. In a 20 mL scintillation was added methyl (*R)-3-(3-((7′-(3-((2-hydroxyethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (60 mg, 0.07 mmol), methanol (1.0 mL), THF (1.0 mL), aqueous LiOH (0.34 mL, 2M) and water (0.34 mL). This mixture was heated to 40 C for 24 h. The reaction was then cooled to r.t., pH adjusted to ˜4.0 with 1N HCl and extracted with ethyl acetate (4×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in 1:1 MeOH/DMSO and purified by reverse phase HPLC (eluent, MeCN/water with 20 mM NH₄OH, 5:95 to 70:30, gradient) to afford the title compound (35 mg, 59%). MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₈S, 788.3; m/z found, 789.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.90 (t, J=5.6 Hz, 1H), 7.31-7.21 (m, 4H), 7.15 (d, J=7.7 Hz, 1H), 4.81 (s, 1H), 4.63 (t, J=5.4 Hz, 1H), 4.45 (d, J=15.6 Hz, 1H), 4.35 (d, J=15.6 Hz, 1H), 3.81-3.71 (m, 2H), 3.53-3.34 (m, 5H), 3.34-3.27 (m, 2H), 3.15-3.05 (m, 2H), 3.00-2.95 (m, 2H), 2.66 (s, 3H), 2.18 (s, 3H), 1.51-1.21 (m, 11H).

Example 129: 3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a 25-mL round bottom flask under nitrogen was added ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (475 mg, 0.72 mmol) and THF (9 mL). The mixture was cooled to −78° C. followed by addition of LDA (0.43 mL, 2.0 M solution in THF/heptane/ethylbenzene) dropwise. After stirring for 30 minutes at −78° C., MeI (0.09 mL, 1.45 mmol) was added to the reaction neat. The reaction was stirred for an additional 1 h at −78° C., then quenched with aqueous saturated NH₄Cl solution and allowed to warm to r.t. The mixture was poured into aqueous saturated NH₄Cl and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate/hexanes: 0:100 to 1:1, gradient) to afford the title compound (85 mg, 17%). MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₄S, 670.3; m/z found, 671.3 [M+H]⁺.

Step B: 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. In a 20 mL scintillation vial was added ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (165 mg, 0.25 mmol), aqueous sodium hydroxide (1M, 2.2 mL) and THF (2.2 mL). The mixture was heated to 50° C. and stirred overnight. After cooling, the reaction mixture pH was adjusted to 4 with 1M aqueous HCl and then extracted with ethyl acetate (4×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by SFC (Chiralcel OD-H 5 μM, 250×21.2 mm, 50% CO₂/50% i-PrOH) to afford the title compound (127 mg, 80%). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₄S, 642.2; m/z found, 643.3 [M+H]⁺.

Example 130: (3*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 129) were separated by chiral SFC (Chiralcel OD-H 5 μM 250×21.2 mm, eluent 80% CO₂/20% MeOH). The first eluting isomer (67 mg) was designated *R: MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₄S, 642.2; m/z found, 643.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=4.7, 1.9 Hz, 1H), 8.04 (dd, J=7.8, 1.9 Hz, 1H), 7.98 (d, J=7.1 Hz, 1H), 7.32-7.22 (m, 2H), 7.18-7.12 (m, 2H), 6.83 (dd, J=7.8, 4.6 Hz, 1H), 4.60-4.37 (m, 3H), 4.34-4.17 (m, 2H), 3.36-3.15 (m, 4H), 2.76 (s, 3H), 2.23 (s, 3H), 1.82-1.60 (m, 2H), 1.55-1.22 (m, 2H), 1.13 (d, J=6.6 Hz, 3H), 0.94-0.71 (m, 2H).

Example 131: (3*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 129) were separated by chiral SFC (Chiralcel OD-H 5 μM 250×21.2 mm, eluent 80% CO₂/20% MeOH). The second eluting isomer (43 mg) was designated *S: MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₄S, 642.2; m/z found, 643.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=4.6, 1.9 Hz, 1H), 8.05 (dd, J=7.8, 1.8 Hz, 1H), 8.00 (d, J=7.1 Hz, 1H), 7.31-7.23 (m, 2H), 7.14 (s, 2H), 6.84 (dd, J=7.8, 4.6 Hz, 1H), 4.60-4.53 (m, 1H), 4.50-4.40 (m, 2H), 4.33-4.19 (m, 2H), 3.38-3.16 (m, 4H), 2.75 (s, 3H), 2.23 (s, 3H), 1.84-1.61 (m, 3H), 1.58-1.33 (m, 2H), 1.23-1.18 (m, 3H), 0.90-0.80 (m, 1H).

Example 132: 3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid

Step A: ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a 25-mL round bottom flask under nitrogen was added ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (500 mg, 0.76 mmol), and THF (10 mL). The mixture was cooled to −78° C. followed by addition of LDA (0.46 mL, 2.0 M solution in THF/heptane/ethylbenzene) dropwise. After stirring for 30 minutes at −78° C., MeI (0.19 mL, 3.05 mmol) was added to the reaction neat. The reaction was stirred for an additional 1 h at −78° C., then quenched with aqueous saturated NH₄Cl solution and allowed to warm to r.t. The mixture was poured into aqueous saturated NH₄Cl and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate/hexanes, 0:100 to 1:1 ethyl acetate/hexanes, gradient) to afford the title compound (150 mg, 29%). MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₄S, 670.3; m/z found, 671.3 [M+H]⁺.

Step B: ethyl 3-(5,8-dimethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoate. To a 25 mL round bottom flask under nitrogen was added ethyl 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (150 mg, 0.22 mmol), and THF (3.0 mL). The mixture was cooled to −78° C. followed by the addition of LDA solution (0.13 mL, 0.26 mmol, 2.0 M solution in THF/heptane/ethylbenzene) dropwise. The reaction was stirred at −78° C. for 1 h before it was quenched with saturated aqueous NH₄Cl and then allowed to warm to r.t. The quenched reaction mixture was then poured into saturated aqueous NH₄Cl and extracted with ethyl acetate (3×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexanes, 0:100 to 1:1 ethyl acetate/hexanes, gradient) to afford the title compound (110 mg, 72%). MS (ESI): mass calcd. for C₃₄H₃₉F₃N₆O₄S, 684.3; m/z found, 685.2 [M+H]⁺.

Step C: 3-(5,8-dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid. In a 20 mL vial was added ethyl 3-(5,8-dimethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-34(*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoate (110 mg, 0.16 mmol), aqueous sodium hydroxide (1M, 1.5 mL) and THF (1.5 mL). The mixture was heated to 50° C. and stirred overnight. After cooling, the reaction mixture pH was adjusted to 4 with 1M aqueous HCl and then extracted with ethyl acetate (4×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure to afford the title compound (73 mg, 69%). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.2; m/z found, 657.2 [M+H]⁺.

Example 133: (3*R)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid

The mixture of 3-(5,8-dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid isomers (Example 132) were separated by chiral SFC (AD-H 2×25 cm, eluent 75% CO₂/25% i-PrOH). The first eluting isomer (26 mg) was designated *R: MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.2; m/z found, 657.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=4.6, 1.9 Hz, 1H), 8.05 (dd, J=7.8, 1.9 Hz, 1H), 7.31 (s, 1H), 7.15-7.12 (m, 2H), 7.00 (s, 1H), 6.84 (dd, J=7.8, 4.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.50-4.39 (m, 2H), 4.33-4.18 (m, 2H), 3.45-3.18 (m, 4H), 2.75-2.65 (m, 6H), 2.21 (s, 3H), 1.84-1.34 (m, 6H), 1.27-1.20 (m, 3H).

Example 134: (3*S)-3-(5,8-Dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid

The mixture of 3-(5,8-dimethyl-3)-(trifluoromethyl)-[1,2,4-triazolo[4,3-a]pyridine-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid isomers (Example 132) were separated by chiral SFC (AD-H 2×25 cm, eluent 75% CO₂/25% i-PrOH). The second eluting isomer (30 mg) was designated *S: MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.2; m/z found, 657.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=4.6, 1.9 Hz, 1H), 8.05 (dd, J=7.8, 1.9 Hz, 1H), 7.31 (s, 1H), 7.15-7.12 (m, 2H), 7.00 (s, 1H), 6.84 (dd, J=7.8, 4.6 Hz, 1H), 4.58-4.40 (m, 3H), 4.32-4.18 (m, 2H), 3.40-3.16 (m, 4H), 2.75-2.65 (m, 6H), 2.21 (s, 3H), 1.81-1.60 (m, 3H), 1.57-1.46 (m, 1H), 1.43-1.32 (m, 2H), 1.25-1.16 (m, 3H).

Example 135: (R/S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

DMF (1.5 mL) was added to an ice-cooled, stirring mixture of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 13, 79 mg, 0.31 mmol) and sodium hydride (60% dispersion in mineral oil, 42 mg, 1.05 mmol) under nitrogen. After 30 minutes, ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 31, 123 mg, 0.308 mmol) was added and the mixture was allowed to warm to room temperature for 2.5 hours. 1 M aqueous sodium hydroxide solution (0.62 mL) was added and the reaction was stirred at room temperature overnight. The mixture was filtered and the filtrate was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA) to provide the title compound (110.5 mg, 99% yield). MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅S, 590.2; m/z found, 591.0 [M+H]⁺.

Example 136: (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 135) was separated by chiral SFC (Daicel Chiralpak AD-H 5 μm, 300 gram, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereomers. The first eluting isomer (41 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅S, 590.2; m/z found, 591.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.24 (dd, J=4.6, 1.8 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.37-7.26 (m, 3H), 6.96 (d, J=7.9 Hz, 1H), 6.83 (dd, J=7.8, 4.6 Hz, 1H), 6.74 (dd, J=7.8, 2.0 Hz, 1H), 4.86 (dd, J=12.0, 3.9 Hz, 1H), 4.68-4.49 (m, 5H), 4.28 (d, J=11.3 Hz, 1H), 4.11 (d, J=13.1 Hz, 1H), 3.75-3.64 (m, 4H), 3.29-3.21 (m, 1H), 3.14 (dd, J=13.6, 4.1 Hz, 1H), 3.05-2.97 (m, 1H), 2.94-2.88 (m, 1H), 2.64 (s, 3H), 2.13 (s, 3H), 1.58-1.52 (m, 3H).

Example 137: (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (41 mg) from the separation of isomers by chiral SFC described in Example 136 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅S, 590.2; m/z found, 591.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.32-8.28 (m, 1H), 8.11 (d, J=7.9, 1.8 Hz, 1H), 7.41-7.31 (m, 2H), 7.24 (s, 1H), 7.12-7.03 (m, 2H), 6.89 (dd, J=7.8, 4.6 Hz, 1H), 5.00-4.91 (m, 1H), 4.66 (q, J=7.3 Hz, 2H), 4.62-4.49 (m, 2H), 4.39-4.28 (m, 2H), 3.95-3.87 (m, 1H), 3.76-3.61 (m, 4H), 3.29-3.13 (m, 2H), 3.06-2.95 (m, 2H), 2.86 (s, 3H), 2.11 (s, 3H), 1.64-1.58 (m, 3H).

Example 138: (R/S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (111 mg, 62% yield) was prepared using analogous conditions as described in Example 135 where (*R)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 14) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅S, 590.2; m/z found, 591.0 [M+H]⁺.

Example 139: (*S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 138) was separated by chiral SFC (Daicel Chiralpak AD-H 5 μm, 300 gram, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereomers. The first eluting isomer (37 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅S, 590.2; m/z found, 591.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (dd, J=4.7, 1.8 Hz, 1H), 8.02 (dd, J=7.8, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.16 (s, 1H), 7.02-6.95 (m, 2H), 6.80 (dd, J=7.9, 4.6 Hz, 1H), 4.91-4.83 (m, 1H), 4.57 (q, J=7.3 Hz, 2H), 4.53-4.41 (m, 2H), 4.30-4.19 (m, 2H), 3.85-3.80 (m, 1H), 3.66-3.53 (m, 4H), 3.20-3.13 (m, 1H), 3.13-3.04 (m, 1H), 2.95-2.82 (m, 2H), 2.77 (s, 3H), 2.02 (s, 3H), 1.55-1.50 (m, 3H).

Example 140: (*R)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (38 mg) from the separation of isomers by chiral SFC described in Example 139 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₅S, 590.2; m/z found, 591.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.33 (dd, J=4.6, 1.8 Hz, 1H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 7.46-7.35 (m, 3H), 7.05 (d, J=7.8 Hz, 1H), 6.92 (dd, J=7.8, 4.7 Hz, 1H), 6.86-6.81 (m, 1H), 4.99-4.92 (m, 1H), 4.77-4.57 (m, 5H), 4.40-4.33 (m, 1H), 4.20 (d, J=13.1 Hz, 1H), 3.85-3.72 (m, 4H), 3.38-3.29 (m, 1H), 3.27-3.19 (m, 1H), 3.14-3.05 (m, 1H), 3.05-2.97 (m, 1H), 2.73 (s, 3H), 2.22 (s, 3H), 1.67-1.61 (m, 3H).

Example 141: (R/S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (120.6 mg, 67% yield) was prepared using analogous conditions as described in Example 135 where (S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.2; m/z found, 589.0 [M+H]⁺.

Example 142: (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 141) was separated by chiral SFC (Daicel Chiralpak AD-H 5 μm, 300 gram, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereomers. The first eluting isomer (39 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.2; m/z found, 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J=4.4 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.39-7.31 (m, 2H), 7.15-7.07 (m, 3H), 6.85-6.80 (m, 1H), 4.98 (t, 1H), 4.66 (q, J=7.4 Hz, 2H), 4.54-4.48 (m, 1H), 4.44 (d, J=14.3 Hz, 1H), 4.22-4.13 (m, 2H), 3.23-3.14 (m, 3H), 3.14-3.04 (m, 2H), 2.84 (s, 3H), 2.26 (s, 3H), 1.70-1.59 (m, 4H), 1.54-1.25 (m, 5H).

Example 143: (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (38 mg) from the separation of isomers by chiral SFC described in Example 142 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.2; m/z found, 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31-8.27 (m, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.33 (s, 2H), 7.15-7.08 (m, 3H), 6.85-6.81 (m, 1H), 5.04-4.94 (m, 1H), 4.65 (q, J=7.1 Hz, 2H), 4.52-4.44 (m, 2H), 4.24-4.11 (m, 2H), 3.18-3.07 (m, 5H), 2.86 (s, 3H), 2.27 (s, 3H), 1.71-1.50 (m, 5H), 1.43-1.17 (m, 4H).

Example 144: (R/S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (99.8 mg, 56% yield) was prepared using analogous conditions as described in Example 135 where (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.2; m/z found, 589.0 [M+H]⁺.

Example 145: (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1.2.3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 144) was separated by chiral SFC (Daicel Chiralpak AD-H Sum, 300 gram, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereomers. The first eluting isomer (26 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.2; m/z found, 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (dd, J=4.6, 1.8 Hz, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H), 7.33 (s, 2H), 7.15-7.08 (m, 3H), 6.86-6.80 (m, 1H), 4.98 (t, J=7.8 Hz, 1H), 4.65 (q, J=7.3 Hz, 2H), 4.51-4.43 (m, 2H), 4.23-4.11 (m, 2H), 3.22-3.04 (m, 5H), 2.86 (s, 3H), 2.27 (s, 3H), 1.71-1.49 (m, 5H), 1.44-1.14 (m, 4H).

Example 146: (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (25 mg) from the separation of isomers by chiral SFC described in Example 145 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.2; m/z found, 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J=4.8, 1.7 Hz, 1H), 8.05 (dd, J=7.7, 1.8 Hz, 1H), 7.39-7.30 (m, 2H), 7.15-7.08 (m, 3H), 6.85-6.79 (m, 1H), 4.98 (t, 1H), 4.66 (q, J=7.3 Hz, 2H), 4.55-4.47 (m, 1H), 4.44 (d, J=14.4 Hz, 1H), 4.22-4.14 (m, 2H), 3.24-3.13 (m, 3H), 3.13-3.04 (m, 2H), 2.84 (s, 3H), 2.26 (s, 3H), 1.71-1.59 (m, 4H), 1.54-1.24 (m, 5H).

Example 147: (R/S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (34.4 mg, 50% yield) was prepared using analogous conditions as described in Example 135 where (S)-6,7,7a,8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 84) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.2 [M+H]⁺.

Example 148: (*S)-3-[3-[(5,5-Dioxo-7a,8,9,10-tetrahydro-7H-pyrrolo[2,1-d][1,2,5]benzothiadiazepin-6-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 147) was separated by chiral SFC (Daicel Chiralpak AD-H 5 μm, mobile phase: 55% CO₂, 45% MeOH) to afford two diastereomers. The first eluting isomer (11 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.80 (m, 1H), 7.34-7.27 (m, 1H), 7.27-7.21 (m, 2H), 7.04-6.96 (m, 3H), 6.90-6.84 (m, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.86 (t, J=7.7 Hz, 1H), 4.61-4.51 (m, 2H), 4.24-4.05 (m, 2H), 3.42 (s, 1H), 3.25-3.18 (m, 2H), 3.12-2.94 (m, 3H), 2.88-2.69 (m, 4H), 2.20 (s, 3H), 1.90-1.73 (m, 2H), 1.73-1.59 (m, 1H), 1.58-1.45 (m, 3H), 1.36-1.26 (m, 1H).

Example 149: (*R)-3-[3-[(5,5-Dioxo-7a,8,9,10-tetrahydro-7H-pyrrolo[2,1-d][1,2,5]benzothiadiazepin-6-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic acid

The second eluting isomer (13 mg) from the separation of isomers by chiral SFC described in Example 148 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.2 [M+H]⁺.

Example 150: (R/S)-3-[3-[(4,4-Dimethyl-1,1-dioxo-3H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl]-4-methyl-phenyl]-3-(1-ethyl-4-methyl-benzotriazol-5-yl)propanoic acid

The title compound (11 mg, 44% yield) was prepared using analogous conditions as described in Example 135 where 4,4-dimethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 82) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₂₉H₃₃N₅O₅S, 563.2; m/z found, 564.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.39 (dd, J=4.9, 2.0 Hz, 1H), 8.12 (dd, J=7.6, 2.0 Hz, 1H), 7.28 (q, J=8.7 Hz, 2H), 7.19-7.15 (m, 2H), 6.99-6.93 (m, 2H), 4.92 (t, J=7.7 Hz, 1H), 4.63-4.57 (m, 2H), 4.41 (s, 2H), 3.42 (s, 2H), 3.06-2.88 (m, 2H), 2.74 (s, 3H), 2.16 (s, 3H), 1.60-1.53 (m, 3H) 1.15-1.08 (m, 6H).

Example 151: (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (26.6 mg, 47% yield) was prepared using analogous conditions as described in Example 135 where 4,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 81) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₀H₃₄N₄O₅S, 562.2; m/z found, 563.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J=7.8, 1.7 Hz, 1H), 7.45-7.40 (m, 1H), 7.35-7.27 (m, 2H), 7.21-7.14 (m, 2H), 7.07-6.98 (m, 3H), 4.93 (t, J=7.8 Hz, 1H), 4.66-4.58 (m, 2H), 4.44-4.36 (m, 2H), 3.37-3.24 (m, 2H), 3.16-2.96 (m, 2H), 2.77 (s, 3H), 2.20 (s, 3H), 1.61-1.55 (m, 3H), 1.10-0.99 (m, 6H).

Example 152: (R/S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (34.1 mg, 59% yield) was prepared using analogous conditions as described in Example 135 where (R)-6,7,7a,8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 83) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.83 (m, 1H), 7.39-7.32 (m, 1H), 7.29 (d, J=1.2 Hz, 2H), 7.15 (d, J=6.6 Hz, 1H), 7.04-6.95 (m, 2H), 6.95-6.82 (m, 2H), 4.93 (t, J=7.8 Hz, 1H), 4.65-4.57 (m, 2H), 4.30-4.12 (m, 2H), 3.35-3.21 (m, 2H), 3.11-2.91 (m, 5H), 2.81-2.75 (m, 3H), 2.23 (d, J=4.5 Hz, 3H), 1.93-1.63 (m, 3H), 1.61-1.53 (m, 3H), 1.35 (t, J=10.1 Hz, 1H).

Example 153: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 152) was separated by chiral SFC (Chiralpak AD-H 5 μm, mobile phase: 55% CO₂, 45% MeOH) to afford two diastereomers. The first eluting isomer (16 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=7.8 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.27-7.20 (m, 2H), 7.07-6.96 (m, 3H), 6.91-6.85 (m, 1H), 6.83-6.77 (m, 1H), 4.91-4.84 (m, 1H), 4.61-4.51 (m, 2H), 4.26-4.08 (m, 2H), 3.30-3.15 (m, 2H), 3.12-2.92 (m, 3H), 2.77 (s, 3H), 2.21 (s, 3H), 1.90-1.27 (m, 6H), 1.25-1.17 (m, 3H).

Example 154: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (14 mg) from the separation of isomers by chiral SFC described in Example 153 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.79 (m, 1H), 7.34-7.21 (m, 3H), 7.06-6.96 (m, 3H), 6.91-6.85 (m, 1H), 6.84-6.77 (m, 1H), 4.94-4.82 (m, 1H), 4.62-4.52 (m, 2H), 4.22-4.08 (m, 2H), 3.28-3.17 (m, 2H), 3.14-2.95 (m, 3H), 2.78-2.70 (m, 3H), 2.25-2.17 (m, 3H), 1.89-1.29 (m, 6H), 1.18 (s, 3H).

Example 155: (R/S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (15.5 mg, 11% yield) was prepared using analogous conditions as described in Example 135 where (S)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 75) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺.

Example 156: (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 155) was separated by chiral SFC (Chiralpak AD-H 5 μm, mobile phase: 50% CO₂, 50% MeOH) to afford two diastereomers. The first eluting isomer (9 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28-8.18 (m, 1H), 8.06-7.97 (m, 1H), 7.34-7.22 (m, 2H), 7.09-6.94 (m, 3H), 6.74 (dd, J=7.7, 4.6 Hz, 1H), 4.90-4.79 (m, 1H), 4.62-4.46 (m, 3H), 4.32 (d, J=14.1 Hz, 1H), 4.05 (d, J=13.9 Hz, 1H), 3.61-3.39 (m, 2H), 3.24-3.14 (m, 1H), 3.12-2.92 (m, 2H), 2.80-2.67 (m, 4H), 2.19 (s, 3H), 1.93-1.81 (m, 1H), 1.76-1.65 (m, 1H), 1.57-1.43 (m, 4H), 1.41-1.31 (m, 1H).

Example 157: (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (9 mg) from the separation of isomers by chiral SFC described in Example 156 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.24-8.17 (m, 1H), 8.02-7.95 (m, 1H), 7.29-7.20 (m, 2H), 7.06-6.93 (m, 3H), 6.77-6.68 (m, 1H), 4.92-4.79 (m, 1H), 4.55 (q, J=7.3 Hz, 2H), 4.50-4.39 (m, 1H), 4.34-4.26 (m, 1H), 4.06-3.99 (m, 1H), 3.58-3.42 (m, 2H), 3.18-3.08 (m, 1H), 3.06-2.82 (m, 2H), 2.80-2.65 (m, 4H), 2.17 (s, 3H), 1.90-1.74 (m, 1H), 1.74-1.63 (m, 1H), 1.63-1.43 (m, 4H), 1.37-1.26 (m, 1H).

Example 158: (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (8 mg, 5% yield) was prepared using analogous conditions as described in Example 135 where 4,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 81) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide, followed by separation of the mixture of isomers by chiral SFC (Chiralpak IC 5 μm, mobile phase: 60% CO₂, 40% MeOH) to afford two diastereomers. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₄N₄O₅S, 562.2; m/z found, 563.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, J=7.8, 1.7 Hz, 1H), 7.37 (td, J=7.6, 1.7 Hz, 1H), 7.30-7.22 (m, 2H), 7.16-7.09 (m, 1H), 7.03 (s, 1H), 7.01-6.97 (m, 3H), 4.88 (t, J=7.7 Hz, 1H), 4.56 (q, J=7.3 Hz, 2H), 4.43-4.26 (m, 2H), 3.37-3.14 (m, 2H), 3.15-2.96 (m, 2H), 2.73 (s, 3H), 2.15 (s, 3H), 1.54-1.48 (m, 3H), 1.02-0.89 (m, 6H).

Example 159: (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (9 mg) from the separation of isomers by chiral SFC described in Example 158 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₄N₄O₅S, 562.2; m/z found, 563.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, J=7.8, 1.7 Hz, 1H), 7.37 (td, J=7.6, 1.7 Hz, 1H), 7.30-7.22 (m, 2H), 7.16-7.10 (m, 1H), 7.04-6.96 (m, 4H), 4.88 (t, J=7.7 Hz, 1H), 4.56 (q, J=7.3 Hz, 2H), 4.41-4.25 (m, 2H), 3.35-3.15 (m, 2H), 3.15-2.95 (m, 2H), 2.73 (s, 3H), 2.15 (s, 3H), 1.55-1.47 (m, 3H), 1.04-0.89 (m, 6H).

Example 160: (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (24 mg, 42% yield) was prepared using analogous conditions as described in Example 135 where 4,4-dimethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 82) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 105) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₅S, 535.2; m/z found, 536.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (dd, J=4.9, 2.0 Hz, 1H), 8.18 (dd, J=7.6, 2.0 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.26-7.22 (m, 1H), 7.20 (s, 1H), 7.14-7.07 (m, 2H), 6.67 (d, J=7.3 Hz, 1H), 4.65 (t, J=7.7 Hz, 1H), 4.55-4.42 (m, 2H), 3.55 (s, 2H), 3.22-3.07 (m, 2H), 2.65 (s, 3H), 2.25 (s, 3H), 1.23 (s, 6H).

Example 161: (R/S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (23.6 mg, 41% yield) was prepared using analogous conditions as described in Example 135 where 4,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 81) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 105) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₂₈H₃₀N₄O₅S, 534.2; m/z found, 535.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.86-7.79 (m, 2H), 7.67 (d, J=7.2 Hz, 1H), 7.49-7.43 (m, 1H), 7.24-7.19 (m, 2H), 7.12-7.03 (m, 3H), 6.66 (d, J=7.3 Hz, 1H), 4.64 (t, J=7.6 Hz, 1H), 4.50-4.36 (m, 2H), 3.46 (s, 2H), 3.20-3.02 (m, 2H), 2.63 (s, 3H), 2.24 (s, 3H), 1.18 (s, 6H).

Example 162: (R/S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3

The title compound (9.9 mg, 11% yield) was prepared using analogous conditions as described in Example 135 where (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 105) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₅S, 535.2; m/z found, 536.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.40 (dd, J=4.8, 1.9 Hz, 1H), 8.17-8.12 (m, 1H), 8.11-8.04 (m, 2H), 7.22-7.19 (m, 1H), 7.16-7.09 (m, 2H), 7.08-6.99 (m, 2H), 4.61-4.54 (m, 1H), 4.43-4.29 (m, 2H), 4.03-3.97 (m, 1H), 3.58-3.45 (m, 1H), 3.21-3.09 (m, 2H), 3.03-2.94 (m, 1H), 2.73 (s, 3H), 2.18 (s 3H), 1.72-1.60 (m, 1H), 1.59-1.47 (m, 1H), 0.97 (t, J=7.3 Hz, 3H).

Example 163: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (4 mg, 7% yield) was prepared using analogous conditions as described in Example 135 where (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 105) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate, followed by separation of the mixture of isomers by chiral SFC (Chiralpak AD-H 5 μm, mobile phase: 45% CO₂, 55% EtOH) to afford two diastereomers. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₂₈H₃₀N₆O₄S, 546.2; m/z found, 547.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.21 (m, 1H), 8.03-7.96 (m, 1H), 7.96-7.86 (m, 1H), 7.77-7.65 (m, 1H), 7.14-6.94 (m, 3H), 6.81-6.71 (m, 1H), 6.71-6.60 (m, 1H), 4.64-4.51 (m, 2H), 4.38-4.29 (m, 1H), 4.16 (d, J=14.5 Hz, 1H), 3.65-3.55 (m, 2H), 3.37-3.30 (m, 1H), 3.15-3.05 (m, 1H), 3.05-2.94 (m, 1H), 2.94-2.81 (m, 1H), 2.61 (s, 3H), 2.21 (s, 3H), 2.03-1.93 (m, 1H), 1.91-1.82 (m, 1H), 1.80-1.71 (m, 1H), 1.57-1.47 (m, 1H).

Example 164: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (4 mg) from the separation of isomers by chiral SFC described in Example 163 was designated (*R): MS (ESI): mass calcd. for C₂₈H₃₀N₆O₄S, 546.2; m/z found, 547.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=4.8, 1.8 Hz, 1H), 8.00 (dd, J=7.7, 1.8 Hz, 1H), 7.95-7.88 (m, 1H), 7.69-7.62 (m, 1H), 7.10-7.00 (m, 3H), 6.77-6.71 (m, 1H), 6.66-6.59 (m, 1H), 4.62-4.50 (m, 2H), 4.35 (d, J=14.6 Hz, 1H), 4.13 (d, J=14.6 Hz, 1H), 3.64-3.53 (m, 2H), 3.36-3.28 (m, 1H), 3.16-3.07 (m, 1H), 3.07-2.95 (m, 1H), 2.86 (t, J=12.5 Hz, 1H), 2.60 (s, 3H), 2.22 (s, 3H), 2.04-1.91 (m, 1H), 1.90-1.82 (m, 1H), 1.79-1.66 (m, 1H), 1.56-1.46 (m, 1H).

Example 165: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (7 mg, 13% yield) was prepared using analogous conditions as described in Example 135 where (R)-6,7,7a,8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 83) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 105) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate, followed by separation of the mixture of isomers by chiral SFC (Chiralpak AD-H 5 μm, mobile phase: 45% CO₂, 55% EtOH) to afford two diastereomers. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₂₉H₃₁N₅O₄S, 545.2; m/z found, 546.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.94-7.89 (m, 1H), 7.84-7.80 (m, 1H), 7.64-7.56 (m, 1H), 7.37-7.29 (m, 1H), 7.10-6.98 (m, 3H), 6.91-6.82 (m, 2H), 6.57-6.51 (m, 1H), 4.64-4.55 (m, 1H), 4.29-4.10 (m, 3H), 3.36-2.98 (m, 6H), 2.58 (s, 3H), 2.23 (s, 3H), 1.97-1.75 (m, 3H), 1.49-1.42 (m, 1H).

Example 166: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (6 mg) from the separation of isomers by chiral SFC described in Example 165 was designated (*R): MS (ESI): mass calcd. for C₂₉H₃₁N₅O₄S, 545.2; m/z found, 546.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.96-7.86 (m, 1H), 7.88-7.76 (m, 1H), 7.70-7.60 (m, 1H), 7.38-7.24 (m, 1H), 7.13-6.93 (m, 3H), 6.89-6.77 (m, 2H), 6.68-6.56 (m, 1H), 4.63-4.51 (m, 1H), 4.34-4.06 (m, 3H), 3.37-2.80 (m, 6H), 2.59 (s, 3H), 2.23 (s, 3H), 2.03-1.69 (m, 3H), 1.53-1.42 (m, 2H).

Example 167: (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (200 mg, 75% yield) was prepared using analogous conditions as described in Example 135 where (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 106) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J=4.9 Hz, 1H), 8.27-8.20 (m, 1H), 8.07 (d, J=7.7 Hz, 1H), 7.23-7.08 (m, 3H), 7.05 (s, 1H), 6.88-6.79 (m, 1H), 4.97-4.83 (m, 1H), 4.74-4.56 (m, 1H), 4.40 (d, J=14.6 Hz, 1H), 4.22 (d, J=15.8 Hz, 1H), 3.77-3.63 (m, 2H), 3.49-3.33 (m, 1H), 3.20-3.05 (m, 2H), 2.98-2.88 (m, 1H), 2.74-2.62 (m, 3H), 2.31-2.21 (m, 3H), 2.21-1.92 (m, 3H), 1.91-1.79 (m, 1H), 1.69-1.55 (m, 1H), 1.37-1.19 (m, 4H).

Example 168: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of (R/S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 167) was separated by chiral SFC (Chiralpak IA, mobile phase: 60% CO₂, 40% MeOH) to afford two diastereomers. The first eluting isomer (89 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.36-8.27 (m, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 7.93 (s, 1H), 7.18-7.03 (m, 3H), 6.88-6.74 (m, 2H), 4.96 (s, 1H), 4.60 (t, J=10.8 Hz, 1H), 4.43 (d, J=14.4 Hz, 1H), 4.19 (d, J=14.4 Hz, 1H), 3.69-3.57 (m, 2H), 3.31 (dd, J=13.2, 3.6 Hz, 1H), 3.25-2.97 (m, 2H), 2.95-2.83 (m, 1H), 2.71 (s, 3H), 2.29 (s, 3H), 2.07-1.90 (m, 2H), 1.90-1.67 (m, 2H), 1.56-1.46 (m, 1H), 1.36-1.25 (m, 1H), 1.22-1.11 (m, 3H).

Example 169: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (85 mg) from the separation of isomers by chiral SFC described in Example 168 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=4.5 Hz, 1H), 8.08 (dd, J=7.8, 1.7 Hz, 1H), 7.98-7.89 (m, 1H), 7.18-7.06 (m, 3H), 6.82 (dd, J=7.8, 4.7 Hz, 2H), 5.00-4.87 (m, 1H), 4.69-4.57 (m, 1H), 4.42 (d, J=14.6 Hz, 1H), 4.20 (d, J=14.5 Hz, 1H), 3.71-3.59 (m, 2H), 3.43-3.34 (m, 1H), 3.23-2.99 (m, 2H), 2.91 (t, J=12.5 Hz, 1H), 2.70 (s, 3H), 2.28 (s, 3H), 2.10-1.88 (m, 3H), 1.87-1.74 (m, 1H), 1.60-1.52 (m, 1H), 1.39-1.13 (m, 4H).

Example 170: (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (15 mg) was prepared using analogous conditions as described in Example 135 where (R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 92) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate, followed by separation of the mixture of isomers by chiral SFC (Chiralpak AD-H 5 μm, mobile phase: 50% CO₂, 50% EtOH) to afford two diastereomers. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₆F₂N₆O₄S, 650.2; m/z found, 651.5 [M+H]⁺.

Example 171: (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (16 mg) from the separation of isomers by chiral SFC described in Example 170 was designated (*R): MS (ESI): mass calcd. for C₃₃H₃₆F₂N₆O₄S, 650.2; m/z found, 651.5 [M+H]⁺.

Example 172: (*S)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (15 mg) was prepared using analogous conditions as described in Example 135 where (S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-(cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 92) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate, followed by separation of the mixture of isomers by chiral SFC (Chiralpak AD-H 5 μm, mobile phase: 50% CO₂, 50% iPrOH) to afford two diastereomers. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₆F₂N₆O₄S, 650.2; m/z found, 651.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.26 (m, 1H), 8.07-7.76 (m, 3H), 7.62-7.56 (d, J=8.5 Hz, 1H), 7.41-7.36 (d, J=8.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.17-7.11 (m, 1H), 6.84-6.78 (m, 1H), 5.44-5.35 (t, J=7.9 Hz, 1H), 4.59-4.39 (m, 4H), 4.27-4.11 (m, 2H), 3.33-2.98 (m, 6H), 2.29-2.22 (s, 3H), 1.66-1.31 (m, 5H), 0.93-0.81 (m, 1H), 0.72-0.62 (m, 2H), 0.53-0.44 (m, 2H).

Example 173: (*R)-3-(1-(Cyclopropylmethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (15 mg) from the separation of isomers by chiral SFC described in Example 172 was designated (*R): MS (ESI): mass calcd. for C₃₃H₃₆F₂N₆O₄S, 650.2; m/z found, 651.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.26 (m, 1H), 8.08-7.77 (m, 3H), 7.63-7.57 (m, 1H), 7.41-7.36 (m, 1H), 7.24-7.20 (m, 1H), 7.20-7.14 (m, 1H), 6.85-6.78 (m, 1H), 5.46-5.35 (m, 1H), 4.55-4.42 (m, 3H), 4.31-4.18 (m, 1H), 4.16-4.05 (m, 1H), 3.31-3.00 (m, 6H), 2.34-2.27 (s, 3H), 1.43-1.29 (m, 3H), 1.16-1.02 (m, 2H), 0.95-0.79 (m, 2H), 0.71-0.61 (m, 2H), 0.52-0.43 (m, 2H).

Example 174: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic acid

Step A: (R/S)-Ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b)][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoate. A solution ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate (Intermediate 107, 45.2 mg, 0.115 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91, 33.5 mg, 0.147 mmol), and triphenylphosphine (49.8 mg, 0.19 mmol) in THF (1.8 mL) was stirred at room temperature for 1 minute. DBAD (46.7 mg, 0.203 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (0-20% EtOAc/DCM) to afford the title compound (64 mg, 92% yield) which contained a triphenylphosphine oxide impurity and was used without further purification. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₅S, 604.2; m/z found, 605.2 [M+H]⁺.

Step B: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic acid. 1M Aqueous sodium hydroxide (0.3 mL, 0.3 mmol) was added to a solution of (R/S)-ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoate (63.5 mg, 0.105 mmol) in THF (0.5 mL). The reaction was stirred at 50° C. overnight, then allowed to cool to room temperature. The reaction was then concentrated under a stream of nitrogen and purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH) to provide the title compound (44.5 mg, 73% yield). MS (ESI): mass calcd. for C₂₉H₃₂N₆O₅S, 576.2; m/z found, 577.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38-8.32 (m, 1H), 8.16-8.08 (m, 1H), 7.35-7.23 (m, 2H), 7.15-7.05 (m, 2H), 6.87 (dd, J=15.8, 7.9 Hz, 1H), 4.92-4.85 (m, 1H), 4.47-4.27 (m, 2H), 4.17-4.03 (m, 1H), 2.14-2.02 (m, 3H), 3.66-3.55 (m, 2H), 3.23-3.00 (m, 2H), 2.69-2.56 (m, 4H), 1.68-1.34 (m, 2H), 1.29 (dd, J=11.6, 4.9 Hz, 1H), 1.22-1.14 (m, 3H), 1.00-0.86 (m, 3H).

Example 175: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic acid isomers (Example 174) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 70% CO₂, 30% EtOH) to afford two diastereomers. The first eluting isomer (22 mg) was designated (*S): ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=4.6 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 7.39-7.32 (m, 2H), 7.25-7.17 (m, 2H), 6.87 (d, J=7.8 Hz, 1H), 5.05-4.96 (m, 1H), 4.65-4.50 (m, 2H), 4.25 (d, J=13.8 Hz, 1H), 3.90-3.78 (m, 1H), 3.74-3.66 (m, 1H), 3.38-3.27 (m, 2H), 2.91-2.77 (m, 4H), 2.34 (s, 3H), 1.84-1.73 (m, 1H), 1.66-1.54 (m, 1H), 1.36-1.27 (m, 2H), 1.26-1.23 (m, 2H), 1.11 (t, J=7.3 Hz, 3H).

Example 176: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-5-methylpyridin-2-yl)propanoic acid

The second eluting isomer (22 mg) from the separation of isomers by chiral SFC described in Example 175 was designated (*R): ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d, J=4.5 Hz, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.32-7.23 (m, 2H), 7.17-7.09 (m, 2H), 6.92 (d, J=7.8 Hz, 1H), 4.93-4.84 (m, 1H), 4.44 (d, J=14.3 Hz, 1H), 4.39-4.28 (m, 1H), 4.07 (d, J=14.4 Hz, 1H), 3.66-3.55 (m, 2H), 3.19-3.01 (m, 2H), 2.69-2.56 (m, 4H), 2.11 (s, 3H), 1.57-1.45 (m, 1H), 1.36-1.29 (m, 2H), 1.22-1.15 (m, 3H), 0.96-0.90 (m, 3H).

Example 177: (R/S)-3-(4-Methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (44.6 mg, 19.8% yield) was prepared using analogous conditions as described in Example 135 where (*S)-9-methyl-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 85) was used instead of (*S)-6,7,7a, 8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 104) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 644.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.25 (m, 1H), 8.12-8.00 (m, 2H), 7.50-7.33 (m, 1H), 7.14-7.09 (m, 1H), 7.08-6.83 (m, 3H), 4.95-4.78 (m, 2H), 4.66-4.35 (m, 3H), 4.05-3.78 (m, 1H), 3.41-2.83 (m, 5H), 2.83-2.71 (m, 4H), 2.58-2.51 (m, 1H), 2.46-2.35 (m, 4H), 2.13-2.04 (m, 3H).

Example 178: (*S)-3-(4-Methyl-3-(((S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (R/S)-3-(4-methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 177) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 55% CO₂, 45% iPrOH with 0.3% iPrNH₂) to afford two diastereomers. The first eluting isomer (20 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 644.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.27 (m, 1H), 8.12-8.04 (m, 2H), 7.48-7.45 (m, 1H), 7.09-7.03 (m, 1H), 7.02-6.97 (m, 1H), 6.94-6.83 (m, 2H), 4.94-4.84 (m, 2H), 4.67-4.55 (m, 1H), 4.50-4.38 (m, 2H), 4.00 (t, J=13.5 Hz, 1H), 3.43-3.33 (m, 1H), 3.31-3.22 (m, 1H), 3.02-2.88 (m, 2H), 2.87-2.77 (m, 2H), 2.74 (s, 2H), 2.59-2.50 (m, 1H), 2.48-2.36 (m, 4H), 2.10-2.03 (m, 3H).

Example 179: (*R)-3-(4-Methyl-3-(((*S)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (21 mg) from the separation of isomers by chiral SFC described in Example 178 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 644.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (dd, J=4.7, 2.0 Hz, 1H), 8.10 (dd, J=5.9, 2.1 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.38-7.33 (m, 1H), 7.13-7.07 (m, 2H), 7.03-6.98 (m, 1H), 6.89 (dd, J=7.8, 4.6 Hz, 1H), 4.89-4.76 (m, 2H), 4.65-4.51 (m, 2H), 4.42-4.33 (m, 1H), 3.83 (t, J=13.2 Hz, 1H), 3.23-2.85 (m, 5H), 2.83-2.76 (m, 4H), 2.57-2.49 (m, 1H), 2.44-2.34 (m, 4H), 2.15-2.07 (m, 3H).

Example 180: (R/S)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (57 mg, 25% yield) was prepared using analogous conditions as described in Example 135 where (*R)-9-methyl-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 86) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 104) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 644.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.26 (m, 1H), 8.13-8.02 (m, 2H), 7.49-7.35 (m, 1H), 7.15-7.09 (m, 1H), 7.08-6.84 (m, 3H), 4.95-4.76 (m, 2H), 4.66-4.35 (m, 3H), 4.05-3.78 (m, 1H), 3.41-2.83 (m, 5H), 2.83-2.71 (m, 4H), 2.59-2.50 (m, 1H), 2.48-2.35 (m, 4H), 2.15-2.03 (m, 3H).

Example 181: (*S)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (R/S)-3-(4-methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 180) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 60% CO₂, 40% iPrOH with 0.3% iPrNH₂) to afford two diastereomers. The first eluting isomer (29 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 644.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.25 (m, 1H), 8.13-8.06 (m, 1H), 8.06-8.00 (m, 1H), 7.38-7.33 (m, 1H), 7.14-7.07 (m, 2H), 7.04-6.97 (m, 1H), 6.92-6.86 (m, 1H), 4.88-4.75 (m, 2H), 4.66-4.51 (m, 2H), 4.43-4.34 (m, 1H), 3.88-3.78 (m, 1H), 3.25-2.84 (m, 5H), 2.84-2.76 (m, 4H), 2.57-2.48 (m, 1H), 2.46-2.33 (m, 4H), 2.14-2.07 (m, 3H).

Example 182: (*R)-3-(4-Methyl-3-(((*R)-9-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-pyrazino[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (25 mg) from the separation of isomers by chiral SFC described in Example 181 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 644.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.27 (m, 1H), 8.12-8.04 (m, 2H), 7.48-7.43 (m, 1H), 7.08-6.96 (m, 2H), 6.93-6.83 (m, 2H), 4.95-4.83 (m, 2H), 4.67-4.55 (m, 1H), 4.49-4.36 (m, 2H), 4.05-3.94 (m, 1H), 3.38 (d, J=11.4 Hz, 1H), 3.31-3.22 (m, 1H), 3.01-2.87 (m, 2H), 2.87-2.77 (m, 2H), 2.74 (s, 3H), 2.57-2.51 (m, 1H), 2.47-2.35 (m, 4H), 2.10-2.02 (m, 3H).

Example 183: (R/S)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (123 mg, 57% yield) was prepared using analogous conditions as described in Example 135 where 5-methylspiro[2,3-dihydropyrido[2,3-f][1,2,5]thiadiazepine-4,1′-cyclopropane] 1,1-dioxide (Intermediate 93) was used instead of (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide and ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 104) was used instead of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄S, 614.2; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.34-8.21 (m, 2H), 8.03 (d, J=7.2 Hz, 1H), 7.30-7.17 (m, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.09-6.93 (m, 3H), 4.98-4.87 (m, 1H), 4.41 (s, 2H), 3.30 (s, 2H), 3.22-2.96 (m, 5H), 2.78 (s, 3H), 2.25 (s, 3H), 1.11-0.89 (m, 4H).

Example 184: (*S)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(t*rifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (R/S)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 183) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 55% CO₂, 45% iPrOH) to afford enantiomers. The first eluting isomer (51 mg) was designated (*S): MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄S, 614.2; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.22 (m, 1H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 8.00 (d, J=7.1 Hz, 1H), 7.26-7.23 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.05-6.97 (m, 1H), 6.97-6.84 (m, 2H), 4.93 (t, J=7.7 Hz, 1H), 4.39 (s, 2H), 3.41-3.18 (m, 2H), 3.18-2.93 (m, 5H), 2.80 (s, 3H), 2.24 (s, 3H), 1.24-1.19 (m, 2H), 0.97-0.92 (m, 2H).

Example 185: (*R)-3-(4-Methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (51 mg) from the separation of isomers by chiral SFC described in Example 184 was designated (*R): MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄S, 614.2; m/z found, 615.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.25 (m, 1H), 8.12-8.07 (m, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.27-7.26 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.93-6.86 (m, 2H), 4.93 (t, J=7.7 Hz, 1H), 4.39 (s, 2H), 3.30-3.24 (m, 2H), 3.14-2.92 (m, 5H), 2.81 (s, 3H), 2.24 (s, 3H), 1.19-1.11 (m, 2H), 0.98-0.93 (m, 2H).

Example 186: (*S)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 169.2 mg, 0.402 mmol), (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39, 132.3 mg, 0.522 mmol), triphenylphosphine (162.2 mg, 0.618 mmol) and DBAD (141.9 mg, 0.616 mmol) in THF (5 mL) was stirred at room temperature for 3 hours. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (EtOAc/hexanes) to afford the title compound (210 mg, 79% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.2; m/z found, 657.3 [M+H]⁺.

Step B: (*S)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. 1M Aqueous sodium hydroxide (0.96 mL, 0.96 mmol) was added to a solution of ethyl (*S)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (209.5 mg, 0.319 mmol) in THF (1.6 mL) and EtOH (0.5 mL). The reaction was stirred at room temperature for 3 hours. 1 M aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (185 mg, 92% yield). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.43-8.35 (m, 1H), 8.17-8.08 (m, 1H), 8.00 (d, J=7.1 Hz, 1H), 7.39-7.31 (m, 1H), 7.10 (d, J=7.7 Hz, 1H), 7.07-7.01 (m, 1H), 7.01-6.96 (m, 1H), 6.93 (dd, J=7.7, 4.8 Hz, 1H), 4.97 (t, J=8.8, 6.6 Hz, 1H), 4.82-4.72 (m, 1H), 4.33-4.22 (m, 1H), 4.01-3.90 (m, 1H), 3.83 (d, J=14.7 Hz, 1H), 3.62-3.51 (m, 1H), 3.28-3.15 (m, 1H), 3.15-3.03 (m, 1H), 3.00-2.88 (m, 1H), 2.82 (s, 3H), 2.24 (s, 3H), 1.95-1.79 (m, 4H), 0.88 (s, 3H).

Example 187: (*R)-3-(4-Methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (117 mg, 84% yield) was prepared using analogous conditions as described in Example 186 where ethyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 27) was used instead of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.41-8.36 (m, 1H), 8.18-8.10 (m, 1H), 8.07-7.99 (m, 1H), 7.30-7.27 (m, 1H), 7.16-7.05 (m, 2H), 7.04-6.97 (m, 1H), 6.97-6.90 (m, 1H), 4.96 (t, J=8.8, 6.5 Hz, 1H), 4.78 (d, J=15.5 Hz, 1H), 4.25 (d, J=15.5 Hz, 1H), 3.96-3.89 (m, 1H), 3.66 (d, J=14.6 Hz, 1H), 3.59-3.48 (m, 1H), 3.25-3.03 (m, 2H), 2.89-2.74 (m, 4H), 2.26 (s, 3H), 1.89-1.66 (m, 4H), 0.86 (s, 3H).

Example 188: (R/S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (115 mg, 81% yield) was prepared using analogous conditions as described in Example 186 where (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 25) was used instead of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, and DIAD was used instead of DBAD. MS (ESI): mass calcd. for C₂₈H₂₈F₃N₅O₅S, 603.2; m/z found, 604.0 [M+H]⁺.

Example 189: (*S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (R/S)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 188) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 60% CO₂, 40% EtOH) to afford two diastereomers. The first eluting isomer (53 mg) was designated (*S): MS (ESI): mass calcd. for C₂₄H₂₈F₃N₅O₅S, 603.2; m/z found, 604.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.45-8.37 (m, 1H), 8.17 (dd, J=7.7, 1.9 Hz, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.24-7.20 (m, 1H), 7.16 (s, 1H), 7.06-7.01 (m, 1H), 6.98-6.93 (m, 1H), 6.83 (d, J=7.2 Hz, 1H), 4.88-4.80 (m, 1H), 4.44-4.35 (m, 1H), 4.31 (d, J=14.7 Hz, 1H), 4.05 (d, J=14.6 Hz, 1H), 3.58-3.46 (m, 1H), 3.13 (dd, J=15.0, 2.4 Hz, 1H), 3.01-2.91 (m, 1H), 2.88-2.80 (m, 1H), 2.73 (s, 3H), 2.20 (s, 3H), 1.74-1.60 (m, 1H), 1.55-1.45 (m, 1H), 0.97 (t, J=7.3 Hz, 3H).

Example 190: (*R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (55 mg) from the separation of isomers by chiral SFC described in Example 189 was designated (*R): MS (ESI): mass calcd. for C₂₈H₂₈F₃N₅O₅S, 603.2; m/z found, 604.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 8.16 (dd, J=7.7, 1.9 Hz, 1H), 7.95-7.87 (m, 1H), 7.22-7.17 (m, 1H), 7.15 (s, 1H), 7.06-7.01 (m, 1H), 6.99-6.94 (m, 1H), 6.86 (d, J=7.3 Hz, 1H), 4.88-4.79 (m, 1H), 4.44-4.28 (m, 2H), 4.03 (d, J=14.7 Hz, 1H), 3.53-3.44 (m, 1H), 3.16-3.10 (m, 1H), 2.96-2.77 (m, 2H), 2.72 (s, 3H), 2.19 (s, 3H), 1.70-1.58 (m, 1H), 1.51-1.39 (m, 1H), 0.96-0.89 (m, 3H).

Example 191: (3*S)-3-(3-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (215 mg, 57% yield) was prepared using analogous conditions as described in Example 186 where 3-chloro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 95) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. The product was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). MS (ESI): mass calcd. for C₃₀H₃₀ClF₃N₆O₄S, 662.2; m/z found, 663.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (s, 1H), 8.05-7.97 (m, 2H), 7.20-7.12 (m, 2H), 7.08 (t, J=8.7 Hz, 1H), 6.96-6.85 (m, 1H), 4.99-4.90 (m, 1H), 4.58-4.43 (m, 2H), 4.25-4.14 (m, 2H), 3.34-3.13 (m, 4H), 3.13-3.00 (m, 1H), 2.82 (d, J=5.5 Hz, 3H), 2.25 (d, J=11.1 Hz, 3H), 1.80-1.37 (m, 6H).

Example 192: (*S)-3-(3-(((*S)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (3*S)-3-(3-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 191) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 80% CO₂, 20% EtOH) to afford two diastereomers. The first eluting isomer (102 mg) was designated (*S): ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.03-7.96 (m, 2H), 7.20-7.16 (m, 1H), 7.16-7.11 (m, 1H), 7.09-7.04 (m, 1H), 6.92 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.7 Hz, 1H), 4.55-4.48 (m, 1H), 4.44 (d, J=15.1 Hz, 1H), 4.25-4.14 (m, 2H), 3.35-3.26 (m, 1H), 3.26-3.12 (m, 3H), 3.12-2.99 (m, 1H), 2.81 (s, 3H), 2.24 (s, 3H), 1.78-1.58 (m, 3H), 1.58-1.38 (m, 3H).

Example 193: (*S)-3-(3-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (110 mg) from the separation of isomers by chiral SFC described in Example 192 was designated (*R): ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.03-7.97 (m, 2H), 7.16-7.12 (m, 2H), 7.09-7.05 (m, 1H), 6.87 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.8 Hz, 1H), 4.51-4.42 (m, 2H), 4.22-4.15 (m, 2H), 3.25-3.15 (m, 3H), 3.14-2.98 (m, 2H), 2.83 (s, 3H), 2.26 (s, 3H), 1.74-1.54 (m, 3H), 1.51-1.31 (m, 3H).

Example 194: (*S)-3-(3-(((*R)-4-Ethyl-8-methyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-1 0 [1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (71 mg, 49% yield) was prepared using analogous conditions as described in Example 186 where (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. In addition, the hydrolysis reaction was run at 50° C., and the title compound was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). MS (ESI): mass calcd. for C₂₉H₃₀F₃N₅O₅S, 617.2; m/z found, 618.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28-8.25 (m, 1H), 8.05-8.00 (m, 1H), 7.98 (d, J=7.1 Hz, 1H), 7.25-7.21 (m, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.05-7.01 (m, 1H), 6.89 (d, J=7.3 Hz, 1H), 4.92 (t, J=7.7 Hz, 1H), 4.42-4.31 (m, 2H), 4.08 (d, J=14.6 Hz, 1H), 3.64-3.53 (m, 1H), 3.18-3.05 (m, 1H), 2.96 (dd, J=15.9, 8.4 Hz, 1H), 2.78 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 1.72-1.61 (m, 1H), 1.57-1.45 (m, 1H), 0.99 (t, J=7.3 Hz, 3H).

Example 195: (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (119 mg, 85% yield) was prepared using analogous conditions as described in Example 186 where 8′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 96) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide and the hydrolysis reaction was run at 50° C. MS (ESI): mass calcd. for C₂₈H₂₅ClF₃N₅O₅S, 635.1; m/z found, 636.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J=2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.16-7.11 (m, 2H), 7.07-7.04 (m, 1H), 6.88 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.8 Hz, 1H), 4.39-4.27 (m, 2H), 3.60-3.48 (m, 2H), 3.21-3.12 (m, 1H), 3.07-2.99 (m, 1H), 2.81 (s, 3H), 2.29 (s, 3H), 1.21-1.07 (m, 2H), 0.64-0.50 (m, 2H).

Example 196: (*S)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(3-(((*S)-3-chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (293.6 mg, 91% yield) was prepared using analogous conditions as described in Example 174,

Step A where (*S)-3-chloro-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 88) was used instead of (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide and ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26) was used instead of ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate. MS (ESI): mass calcd. for C₃₁H₃₂ClF₃N₆O₅S, 692.2; m/z found, 693.1 [M+H]⁺.

Step B: Ethyl (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DMA (1.4 mL) was added to a mixture of ethyl (*S)-3-(3-(((*S)-3-chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (195.7 mg, 0.282 mmol), zinc cyanide (65.6 mg, 0.56 mmol), XPhos Pd G2 (22.8 mg, 0.029 mmol), and zinc powder (10 mg, 0.16 mmol). Nitrogen was bubbled through the reaction mixture for 1 minute, then the reaction was heated at 120° C. for 1 hour. After that time, the reaction was filtered, and the solids were rinsed with ethyl acetate. The filtrate was washed with saturated aqueous sodium bicarbonate, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-50% EtOAc/hexanes) to afford the title compound (164 mg, 85% yield). MS (ESI): mass calcd. for C₃₂H₃₂F₃N₇O₅S, 683.2; m/z found, 684.1 [M+H]⁺.

Step C: (*S)-3-(3-(((*S)-3-Cyano-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (42 mg, 27% yield) was prepared using analogous conditions as described in Example 186, Step B where ethyl (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of ethyl (*S)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, the hydrolysis reaction was run starting at a temperature of 0° C. with slow warming to room temperature, and it was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₀H₂₈F₃N₇O₅S, 655.2; m/z found, 656.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (d, J=2.1 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.01 (d, J=7.3 Hz, 1H), 6.95-6.90 (m, 1H), 4.95-4.88 (m, 1H), 4.78-4.72 (m, 1H), 4.68-4.61 (m, 1H), 4.49 (d, J=13.7 Hz, 1H), 4.34-4.22 (m, 2H), 3.80-3.77 (m, 2H), 3.77-3.70 (m, 2H), 3.35-3.29 (m, 1H), 3.14-3.04 (m, 2H), 2.99-2.93 (m, 1H), 2.73 (s, 3H), 2.13 (s, 3H).

Example 197: (*S)-3-(3-(((*S)-3-Chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (68.6 mg, 73% yield) was prepared using analogous conditions as described in Example 186, Step B where ethyl (*S)-3-(3-(((*S)-3-chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (prepared in Example 196, Step A) was used instead of ethyl (*S)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₂₉H₂₈ClF₃N₆O₅S, 664.1; m/z found, 665.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J=2.6 Hz, 1H), 8.10 (d, J=7.3 Hz, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.34-7.29 (m, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.99 (d, J=7.3 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.94-4.87 (m, 1H), 4.70-4.62 (m, 1H), 4.57-4.44 (m, 2H), 4.33-4.22 (m, 2H), 3.80-3.67 (m, 4H), 3.28-3.22 (m, 1H), 3.19-3.04 (m, 2H), 2.99-2.92 (m, 1H), 2.72 (s, 3H), 2.18 (s, 3H).

Example 198: (*S)-3-(3-(((*S)-5,5-Dioxido-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (102.4 mg, 60% yield) was prepared using analogous conditions as described in Example 186 where (*S)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 101) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, the hydrolysis reaction was heated at 50° C., and it was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₁H₃₀F₆N₆O₄S, 696.2; m/z found, 697.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53-8.47 (m, 1H), 8.27-8.21 (m, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.24-7.19 (m, 1H), 7.14 (d, J=7.9 Hz, 1H), 7.08-6.97 (m, 2H), 4.95 (t, J=7.8 Hz, 1H), 4.72-4.62 (m, 1H), 4.49 (d, J=15.3 Hz, 1H), 4.38-4.30 (m, 1H), 4.20 (d, J=15.4 Hz, 1H), 3.46-3.38 (m, 1H), 3.33-3.16 (m, 3H), 3.13-3.02 (m, 1H), 2.81 (s, 3H), 2.24 (s, 3H), 1.86-1.63 (m, 3H), 1.63-1.47 (m, 3H).

Example 199: (*S)-3-(3-(((*R)-5,5-Dioxido-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (68.3 mg, 47% yield) was prepared using analogous conditions as described in Example 186 where (*R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 102) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, the hydrolysis reaction was heated at 50° C., and it was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₁H₃₀F₆N₆O₄S, 696.2; m/z found, 697.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53-8.45 (m, 1H), 8.28-8.19 (m, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.19-7.11 (m, 2H), 7.11-7.04 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 5.00-4.91 (m, 1H), 4.67-4.55 (m, 1H), 4.49 (d, J=15.0 Hz, 1H), 4.40-4.27 (m, 1H), 4.18 (d, J=15.0 Hz, 1H), 3.33-2.98 (m, 5H), 2.82 (s, 3H), 2.26 (s, 3H), 1.82-1.58 (m, 3H), 1.58-1.35 (m, 3H).

Example 200: (*S)-3-(3-((8′-Cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (979.6 mg, 78% yield) was prepared using analogous conditions as described in Example 186, Step A where 8′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 96) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₀H₂₉ClF₃N₆O₅S, 663.1; m/z found, 664.2 [M+H]⁺.

Step B: Ethyl (*S)-3-(3-((8′-cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (87.1 mg, 43% yield) was prepared using analogous conditions as described in Example 196, Step B where ethyl (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of ethyl (*S)-3-(3-(((*S)-3-chloro-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₃₁H₂₉F₃N₆O₅S, 654.2; m/z found, 655.2 [M+H]⁺.

Step C: (*S)-3-(3-((8′-Cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (7 mg, 8% yield) was prepared using analogous conditions as described in Example 186, Step B where ethyl (*S)-3-(3-((8′-cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of ethyl (*S)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, the hydrolysis reaction was run overnight, and it was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₂₉H₂₅F₃N₆O₅S, 626.2; m/z found, 627.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.71 (d, J=2.3 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.17-7.13 (m, 2H), 7.09-7.05 (m, 1H), 6.94 (d, J=7.3 Hz, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.38 (s, 2H), 3.62-3.50 (m, 2H), 3.22-3.15 (m, 1H), 3.08-3.01 (m, 1H), 2.83-2.80 (m, 3H), 2.28 (s, 3H), 1.25-1.17 (m, 2H), 0.80-0.69 (m, 2H). In addition to the title compound, (*S)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid was also produced in this reaction and its characterization is shown below in the description of Example 201.

Example 201: (*S)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (62.8 mg, 29% yield) was produced during the experiment described in Example 200, Step C. MS (ESI): mass calcd. for C₂₉H₂₇F₃N₆O₆S, 644.2; m/z found, 645.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 13.10 (s, 1H), 8.46 (s, 1H), 8.40 (d, J=7.1 Hz, 1H), 7.95 (d, J=2.5 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 7.20-7.08 (m, 2H), 7.03 (d, J=7.9 Hz, 1H), 4.81 (t, J=7.8 Hz, 1H), 4.66 (s, 2H), 3.34-3.25 (m, 2H), 3.10 (d, J=7.8 Hz, 2H), 2.75 (s, 3H), 2.15 (s, 3H), 0.45-0.36 (m, 2H), 0.26-0.14 (m, 2H).

Example 202: (*S)-3-(3-(((*S)-2-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (22 mg, 7% yield) was prepared using analogous conditions as described in Example 186 where (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide (Intermediate 98) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, the hydrolysis reaction was run from 0-50° C. with only 1 eq. of base, and the title compound was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₁H₃₀F₃N₇O₄S, 653.2; m/z found, 654.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.18-7.13 (m, 3H), 7.10-7.05 (m, 1H), 6.95 (d, J=7.3 Hz, 1H), 5.00-4.92 (m, 1H), 4.61-4.53 (m, 1H), 4.50 (d, J=15.0 Hz, 1H), 4.34-4.26 (m, 1H), 4.18 (d, J=15.0 Hz, 1H), 3.31-3.14 (m, 3H), 3.09-3.02 (m, 1H), 2.84 (s, 3H), 2.25 (s, 3H), 1.82-1.60 (m, 3H), 1.56-1.36 (m, 4H).

Example 203: (*S)-3-(3-(((*S)-2-Carbamoyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (40 mg, 13% yield) was produced during the experiment described in Example 202, Step C. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₇O₅S, 671.2; m/z found, 672.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (d, J=8.0 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.75-7.71 (m, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.34-7.28 (m, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.05-7.01 (m, 1H), 7.00-6.96 (m, 1H), 6.80 (d, J=7.3 Hz, 1H), 4.87 (t, J=7.8 Hz, 1H), 4.64-4.58 (m, 1H), 4.51-4.47 (m, 1H), 4.41-4.35 (m, 1H), 4.19-4.12 (m, 1H), 3.39-3.34 (m, 1H), 3.29-3.21 (m, 1H), 3.12-3.04 (m, 1H), 2.88 (d, J=7.8 Hz, 2H), 2.79 (s, 3H), 2.28 (s, 3H), 1.80-1.69 (m, 2H), 1.64-1.36 (m, 5H).

Example 204: (*S)-3-(3-(((*R)-2-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1.2.4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (79 mg, 26% yield) was prepared using analogous conditions as described in Example 186 where (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-2-carbonitrile 5,5-dioxide (Intermediate 99) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, the hydrolysis reaction was run from 0-50° C. with only 1 eq. of base, and the title compound was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₁H₃₀F₃N₇O₄S, 653.2; m/z found, 654.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.1 Hz, 1H), 7.21-7.18 (m, 1H), 7.18-7.13 (m, 2H), 7.08-7.04 (m, 1H), 6.99 (d, J=7.3 Hz, 1H), 4.97-4.92 (m, 1H), 4.65-4.57 (m, 1H), 4.47 (d, J=15.3 Hz, 1H), 4.34-4.26 (m, 1H), 4.22 (d, J=15.4 Hz, 1H), 3.44-3.36 (m, 1H), 3.26-3.14 (m, 3H), 3.11-3.03 (m, 1H), 2.80 (s, 3H), 2.22 (s, 3H), 1.84-1.62 (m, 3H), 1.62-1.44 (m, 3H).

Example 205: (*S)-3-(3-(((*R)-2-Carbamoyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (53 mg, 17% yield) was produced during the experiment described in Example 204, Step C. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₇O₅S, 671.2; m/z found, 672.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J=7.9 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.74-7.70 (m, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.10-7.00 (m, 3H), 6.94 (d, J=7.3 Hz, 1H), 4.86-4.80 (m, 1H), 4.65-4.58 (m, 1H), 4.44-4.34 (m, 2H), 4.21-4.14 (m, 1H), 3.44-3.38 (m, 1H), 3.29-3.21 (m, 1H), 3.19-3.02 (m, 3H), 2.71 (s, 3H), 2.26 (s, 3H), 1.83-1.71 (m, 2H), 1.71-1.44 (m, 5H).

Example 206: (*S)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (97 mg, 52% yield) was prepared using analogous conditions as described in Example 174 where (S)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 88) was used instead of (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide and ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26) was used instead of ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate. In addition, the hydrolysis reaction was run at room temperature and the title compound was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). MS (ESI): mass calcd. for C₃₀H₂₈F₃N₇O₄S, 639.2; m/z found, 640.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (d, J=2.2 Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.21-7.17 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 7.05 (dd, J=7.8, 2.0 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 4.99-4.88 (m, 2H), 4.52 (d, J=15.2 Hz, 1H), 4.10 (d, J=15.2 Hz, 1H), 3.76-3.69 (m, 2H), 3.48 (dd, J=13.0, 3.6 Hz, 1H), 3.24-3.14 (m, 1H), 3.11-2.99 (m, 1H), 2.88 (t, J=12.4 Hz, 1H), 2.81 (s, 3H), 2.24 (s, 3H), 2.20-2.07 (m, 1H), 2.06-1.94 (m, 1H), 1.92-1.79 (m, 1H), 1.68-1.57 (m, 1H).

Example 207: (*S)-3-(3-(((R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (156 mg, 60% yield) was prepared using analogous conditions as described in Example 186 where (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 87) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide and the title compound was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). MS (ESI): mass calcd. for C₃₀H₂₈F₃N₇O₄S, 639.2; m/z found, 640.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 8.05 (d, J=7.1 Hz, 1H), 7.16-7.09 (m, 2H), 7.06 (dd, J=7.9, 2.0 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H), 4.98-4.90 (m, 1H), 4.90-4.81 (m, 1H), 4.50 (d, J=15.0 Hz, 1H), 4.12 (d, J=15.0 Hz, 1H), 3.76-3.68 (m, 2H), 3.37 (dd, J=13.0, 3.5 Hz, 1H), 3.21-3.09 (m, 1H), 3.09-3.00 (m, 1H), 2.91-2.82 (m, 1H), 2.79 (s, 3H), 2.25 (s, 3H), 2.16-2.04 (m, 1H), 2.00-1.92 (m, 1H), 1.87-1.74 (m, 1H), 1.63-1.53 (m, 1H).

Example 208: (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 145.8 mg, 0.346 mmol), 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 153.2 mg, 0.539 mmol), and triphenylphosphine (150 mg, 0.572 mmol) in DMF (3 mL) was stirred at room temperature for 1 minute. DBAD (127.5 mg, 0.554 mmol) was added and the solution was stirred at room temperature for 15 minutes. Additional triphenylphosphine (160.9 mg) and DBAD (128.2 mg) were added and the reaction was stirred at room temperature overnight. Additional triphenylphosphine (155.8 mg), DBAD (146.1 mg), and DMF (1 mL) were added and the reaction was stirred at 50° C. overnight. Additional triphenylphosphine (257.4 mg), DBAD (256.3 mg) and THF (7 mL) were added and the reaction was stirred at 50° C. overnight. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (EtOAc/hex) to afford the title compound (263.2 mg) which was used without further purification. MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.2; m/z found, 688.3 [M+H]⁺.

Step B: (*S)-3-(4-Methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. 1M Aqueous sodium hydroxide (1.2 mL, 1.2 mmol) was added to a solution of ethyl (*S)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (263 mg, 0.382 mmol) in THF (2 mL). The reaction was stirred at room temperature overnight. After this time, the reaction was diluted with ethyl acetate and the resulting biphasic mixture was separated. 1 M aqueous HCl solution was added to the aqueous layer until the pH was 3-4. DCM was then added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (72.3 mg, 29% yield) which was used without further purification. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29-8.25 (m, 1H), 8.05 (d, J=7.2 Hz, 1H), 8.03-8.00 (m, 1H), 7.22-7.18 (m, 1H), 7.14-7.10 (m, 1H), 7.08-7.03 (m, 1H), 6.96 (d, J=7.3 Hz, 1H), 4.96-4.88 (m, 1H), 4.69 (d, J=14.4 Hz, 1H), 4.36 (d, J=14.4 Hz, 1H), 4.03-3.87 (m, 2H), 3.79-3.71 (m, 1H), 3.61-3.36 (m, 3H), 3.20-3.10 (m, 1H), 3.01-2.91 (m, 1H), 2.79 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 1.72-1.59 (m, 2H), 1.46-1.37 (m, 1H), 1.22-1.11 (m, 2H).

Example 209: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

DMF (0.75 mL) was added to a mixture of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 70.1 mg, 0.293 mmol) and sodium hydride (60% dispersion in mineral oil, 35.7 mg, 0.893 mmol) under nitrogen at 0° C. After 10 minutes, a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 32, 0.75 ml, 0.4 M in DMF, 0.29 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was filtered, the filtrate was concentrated and purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA) to provide the title compound (64.4 mg, 38% yield). MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.34-8.27 (m, 1H), 8.27-8.22 (m, 1H), 7.49-7.41 (m, 1H), 7.36-7.27 (m, 1H), 7.10-7.05 (m, 2H), 7.04-6.98 (m, 1H), 6.93 (ddd, J=14.3, 7.7, 5.5 Hz, 1H), 4.96-4.76 (m, 2H), 4.50-4.39 (m, 1H), 4.27-4.15 (m, 1H), 3.83-3.61 (m, 3H), 3.39-3.25 (m, 1H), 3.16-3.05 (m, 1H), 3.05-2.84 (m, 2H), 2.81-2.69 (m, 3H), 2.30-2.20 (m, 3H), 2.09-1.93 (m, 1.5H), 1.93-1.75 (m, 1H), 1.71-1.59 (m, 0.5H), 1.59-1.49 (m, 1H), 1.38-1.24 (m, 4H).

Example 210: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 209) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 60% CO₂, 40% EtOH) to afford two diastereomers. The first eluting isomer (19.9 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.03-7.96 (m, 2H), 7.20-7.16 (m, 1H), 7.16-7.11 (m, 1H), 7.09-7.04 (m, 1H), 6.92 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.7 Hz, 1H), 4.55-4.48 (m, 1H), 4.44 (d, J=15.1 Hz, 1H), 4.25-4.14 (m, 2H), 3.35-3.26 (m, 1H), 3.26-3.12 (m, 3H), 3.12-2.99 (m, 1H), 2.81 (s, 3H), 2.24 (s, 3H), 1.78-1.58 (m, 3H), 1.58-1.38 (m, 3H).

Example 211: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (19.7 mg) from the separation of isomers by chiral SFC described in Example 210 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31-8.27 (m, 1H), 8.07 (dd, J=7.8, 1.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.10-7.05 (m, 3H), 6.82-6.76 (m, 1H), 4.93 (t, J=7.8 Hz, 1H), 4.62-4.53 (m, 1H), 4.39 (d, J=14.2 Hz, 1H), 4.11 (d, J=14.2 Hz, 1H), 3.75-3.68 (m, 1H), 3.66-3.57 (m, 1H), 3.57-3.49 (m, 1H), 3.27 (dd, J=13.2, 3.6 Hz, 1H), 3.17-3.01 (m, 2H), 2.84-2.76 (m, 4H), 2.26 (s, 3H), 1.98-1.90 (m, 1H), 1.82-1.75 (m, 1H), 1.64-1.56 (m, 1H), 1.47-1.39 (m, 1H), 1.36-1.27 (m, 4H).

Example 212: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (112.5 mg, 64% yield) was prepared using analogous conditions as described in Example 209 where (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3) was used instead of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. The mixture of isomers was separated by chiral SFC (Chiralpak AD-H, mobile phase: 60% CO₂, 40% EtOH) to afford two diastereomers. The first eluting isomer (41 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28-8.26 (m, 1H), 8.05-8.01 (m, 1H), 7.45-7.41 (m, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.11-7.08 (m, 2H), 7.07 (s, 1H), 6.83-6.78 (m, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.49-4.39 (m, 2H), 4.21-4.15 (m, 1H), 4.12 (d, J=14.2 Hz, 1H), 3.74-3.69 (m, 1H), 3.19-3.00 (m, 5H), 2.82 (s, 3H), 2.25 (s, 3H), 1.70-1.47 (m, 3H), 1.39-1.24 (m, 6H), 1.21 (t, J=5.4 Hz, 1H).

Example 213: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (41 mg) from the separation of isomers by chiral SFC described in Example 212 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29-8.26 (m, 1H), 8.05-8.02 (m, 1H), 7.46-7.42 (m, 1H), 7.37-7.33 (m, 1H), 7.11-7.08 (m, 2H), 7.07 (s, 1H), 6.82-6.79 (m, 1H), 4.94 (t, J=7.9 Hz, 1H), 4.52-4.45 (m, 1H), 4.42 (d, J=14.3 Hz, 1H), 4.20-4.11 (m, 2H), 3.76-3.68 (m, 1H), 3.17-3.02 (m, 5H), 2.80 (s, 3H), 2.23 (s, 3H), 1.70-1.55 (m, 2H), 1.52-1.39 (m, 2H), 1.38-1.23 (m, 6H).

Example 214: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

DMF (0.75 mL) was added to a mixture of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7, 71.7 mg, 0.297 mmol) and sodium hydride (60% dispersion in mineral oil, 41 mg, 1.0 mmol) under nitrogen at 0° C. After 10 minutes, a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 32, 0.75 ml, 0.4 M in DMF, 0.29 mmol) was added and the mixture was allowed to warm to room temperature overnight. 1M aqueous NaOH (0.9 mL, 0.9 mmol) was added and the reaction was stirred for 2 hours. The mixture was filtered and the filtrate was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH) to provide the title compound (60 mg, 35% yield). MS (ESI): mass calcd. for C₃₁H₃₂N₄O₆S, 588.2; m/z found, 589.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.86 (dd, J=7.8, 1.7 Hz, 1H), 7.56 (td, J=7.8, 1.7 Hz, 1H), 7.45-7.41 (m, 1H), 7.38-7.33 (m, 2H), 7.30 (t, J=7.6, 1.2 Hz, 1H), 7.18-7.15 (m, 1H), 7.06-7.03 (m, 1H), 7.00-6.96 (m, 1H), 4.93-4.85 (m, 1H), 4.65-4.54 (m, 2H), 4.45-4.38 (m, 1H), 4.31 (d, J=7.6 Hz, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.17 (d, J=14.1 Hz, 1H), 3.75-3.63 (m, 3H), 3.09-3.00 (m, 1H), 2.96-2.89 (m, 1H), 2.74 (s, 3H), 2.24 (s, 3H), 1.36-1.21 (m, 4H).

Example 215: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 214) was separated by chiral SFC to afford two diastereomers. The first eluting isomer (24.2 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₂N₄O₆S, 588.2; m/z found, 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.90-7.86 (m, 1H), 7.58-7.53 (m, 1H), 7.48-7.43 (m, 1H), 7.41-7.33 (m, 2H), 7.33-7.27 (m, 1H), 7.22 (s, 1H), 7.06-7.01 (m, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.87-4.81 (m, 1H), 4.73-4.56 (m, 3H), 4.43-4.34 (m, 1H), 4.34-4.25 (m, 1H), 4.10 (d, J=13.7 Hz, 1H), 3.86-3.79 (m, 1H), 3.76-3.67 (m, 2H), 3.10-3.00 (m, 1H), 3.00-2.88 (m, 1H), 2.70 (s, 3H), 2.24 (s, 3H), 1.37-1.21 (m, 4H).

Example 216: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (24.9 mg) from the separation of isomers by chiral SFC described in Example 215 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₂N₄O₆S, 588.2; m/z found, 589.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=7.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.49-7.45 (m, 1H), 7.43-7.39 (m, 1H), 7.37-7.34 (m, 1H), 7.33-7.29 (m, 1H), 7.22 (s, 1H), 7.07-7.02 (m, 1H), 6.91 (d, J=7.7 Hz, 1H), 4.88-4.79 (m, 1H), 4.75-4.61 (m, 3H), 4.42-4.34 (m, 1H), 4.33-4.25 (m, 1H), 4.09 (d, J=13.8 Hz, 1H), 3.89-3.77 (m, 1H), 3.77-3.65 (m, 2H), 3.09-3.00 (m, 1H), 3.00-2.89 (m, 1H), 2.70 (s, 3H), 2.25 (s, 3H), 1.37-1.27 (m, 4H).

Example 217: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (42.7 mg, 18% yield) was prepared using analogous conditions as described in Example 209 where (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) was used instead of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺.

Example 218: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The title compound (87 mg, 50% yield) was prepared using analogous conditions as described in Example 209 where (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39) was used instead of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.44-8.38 (m, 1H), 8.33-8.27 (m, 1H), 7.51-7.43 (m, 1H), 7.43-7.37 (m, 1H), 7.21-7.11 (m, 1H), 7.10-6.99 (m, 3H), 5.01-4.90 (t, J=7.8 Hz, 1H), 4.82-4.70 (dd, J=15.0, 7.0 Hz, 1H), 4.37-4.22 (t, J=15.1 Hz, 1H), 4.03-3.89 (m, 1H), 3.81-3.51 (m, 3H), 3.24-3.04 (m, 2H), 2.92-2.81 (m, 1H), 2.77 (d, J=4.9 Hz, 3H), 2.26 (d, J=4.6 Hz, 3H), 1.95-1.69 (m, 4H), 1.40-1.22 (m, 4H), 0.85 (d, J=19.7 Hz, 3H).

Example 219: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid isomers (Example 218) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 55% CO₂, 45% EtOH) to afford two diastereomers. The first eluting isomer (45 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.39-8.36 (m, 1H), 8.13 (dd, J=7.7, 1.9 Hz, 1H), 7.45-7.35 (m, 2H), 7.22-7.19 (m, 1H), 7.07-7.01 (m, 2H), 6.95-6.88 (m, 1H), 4.96 (t, J=7.8 Hz, 1H), 4.72 (d, J=15.1 Hz, 1H), 4.27 (d, J=15.2 Hz, 1H), 3.98-3.88 (m, 1H), 3.75-3.66 (m, 2H), 3.59-3.51 (m, 1H), 3.22-3.00 (m, 2H), 2.85 (d, J=14.7 Hz, 1H), 2.80 (s, 3H), 2.24 (s, 3H), 1.93-1.80 (m, 2H), 1.80-1.68 (m, 2H), 1.37-1.19 (m, 4H), 0.74 (s, 3H).

Example 220: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (44 mg) from the separation of isomers by chiral SFC described in Example 219 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (dd, J=4.8, 1.8 Hz, 1H), 8.15 (dd, J=7.7, 1.9 Hz, 1H), 7.49-7.43 (m, 1H), 7.42-7.36 (m, 1H), 7.21-7.16 (s, 1H), 7.10-7.01 (m, 2H), 6.92 (dd, J=7.7, 4.8 Hz, 1H), 5.00-4.89 (m, 1H), 4.76 (d, J=15.0 Hz, 1H), 4.25 (d, J=15.0 Hz, 1H), 3.98-3.86 (m, 1H), 3.76-3.67 (m, 1H), 3.59-3.49 (m, 2H), 3.44-3.30 (m, 1H), 3.24-3.04 (m, 2H), 2.79 (s, 3H), 2.26 (s, 3H), 1.88-1.76 (m, 2H), 1.72-1.65 (m, 2H), 1.37-1.18 (m, 4H), 0.80 (s, 3H).

Example 221: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The title compound (55.2 mg, 31.4% yield) was prepared using analogous conditions as described in Example 209 where (*R)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 40) was used instead of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.44-8.38 (m, 1H), 8.31-8.24 (m, 1H), 7.50-7.37 (m, 2H), 7.21-7.11 (m, 1H), 7.09-6.98 (m, 3H), 4.95 (t, J=7.9 Hz, 1H), 4.81-4.69 (m, 1H), 4.36-4.21 (m, 1H), 4.01-3.87 (m, 1H), 3.77-3.49 (m, 3H), 3.23-3.02 (m, 2H), 2.90-2.79 (m, 1H), 2.77 (d, J=4.9 Hz, 3H), 2.25 (d, J=4.6 Hz, 3H), 1.91-1.66 (m, 4H), 1.38-1.22 (m, 4H), 0.83 (d, J=20.1 Hz, 3H).

Example 222: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid isomers (Example 221) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 60% CO₂, 40% EtOH) to afford two diastereomers. The first eluting isomer (25 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (dd, J=4.8, 1.8 Hz, 1H), 8.14 (dd, J=7.7, 1.9 Hz, 1H), 7.47-7.36 (m, 2H), 7.15 (s, 1H), 7.08-7.02 (m, 2H), 6.91 (dd, J=7.7, 4.8 Hz, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.74 (d, J=14.9 Hz, 1H), 4.25 (d, J=14.9 Hz, 1H), 3.98-3.86 (m, 1H), 3.78-3.67 (m, 1H), 3.59-3.48 (m, 2H), 3.20-3.01 (m, 2H), 2.81-2.71 (m, 4H), 2.26 (s, 3H), 1.86-1.73 (m, 2H), 1.70-1.62 (m, 2H), 1.36-1.27 (m, 4H), 0.77 (s, 3H).

Example 223: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-(((*R)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (22 mg) from the separation of isomers by chiral SFC described in Example 222 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (dd, J=4.8, 1.8 Hz, 1H), 8.13 (dd, J=7.7, 1.9 Hz, 1H), 7.44-7.36 (m, 2H), 7.20 (s, 1H), 7.08-7.01 (m, 2H), 6.91 (dd, J=7.7, 4.8 Hz, 1H), 4.96 (t, J=7.9 Hz, 1H), 4.72 (d, J=15.2 Hz, 1H), 4.27 (d, J=15.1 Hz, 1H), 3.97-3.88 (m, 1H), 3.74-3.66 (m, 2H), 3.59-3.51 (m, 1H), 3.18-3.00 (m, 2H), 2.87-2.77 (m, 4H), 2.24 (s, 3H), 1.89-1.70 (m, 4H), 1.35-1.26 (m, 4H), 0.73 (s, 3H).

Example 224: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The title compound (82.7 mg, 48% yield) was prepared using analogous conditions as described in Example 214 where 5′-methyl-2′,3′-dihydro-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepine] 1′,1′-dioxide (Intermediate 93) was used instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide the title compound was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.22 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.13-7.03 (m, 3H), 6.99 (dd, J=7.7, 5.2 Hz, 1H), 4.90 (t, J=7.8 Hz, 1H), 4.43-4.30 (m, 2H), 3.77-3.68 (m, 1H), 3.27-2.98 (m, 4H), 2.97 (s, 3H), 2.77 (s, 3H), 2.23 (s, 3H), 1.38-1.22 (m, 4H), 1.01-0.82 (m, 4H).

Example 225: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 224) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 55% CO₂, 45% EtOH) to afford two enantiomers. The first eluting isomer (34 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28-8.23 (m, 1H), 8.12-8.07 (m, 1H), 7.46-7.41 (m, 1H), 7.39-7.33 (m, 1H), 7.16-7.13 (m, 1H), 7.08-7.01 (m, 2H), 6.90-6.86 (m, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.34 (s, 2H), 3.77-3.67 (m, 1H), 3.24-3.00 (m, 4H), 2.97 (s, 3H), 2.80 (s, 3H), 2.23 (s, 3H), 1.36-1.24 (m, 4H), 0.93-0.80 (m, 4H).

Example 226: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((5′-methyl-1′,1′-dioxido-5′H-spiro[cyclopropane-1,4′-pyrido[2,3-f][1,2,5]thiadiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (30 mg) from the separation of isomers by chiral SFC described in Example 225 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₄N₆O₄S, 586.2; m/z found, 587.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.27-8.23 (m, 1H), 8.12-8.06 (m, 1H), 7.46-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.16 (s, 1H), 7.07-7.00 (m, 2H), 6.88 (dd, J=7.8, 4.7 Hz, 1H), 4.95 (t, 1H), 4.34 (s, 2H), 3.75-3.68 (m, 1H), 3.22-3.01 (m, 4H), 2.97 (s, 3H), 2.80 (s, 3H), 2.23-2.21 (m, 3H), 1.36-1.20 (m, 4H), 0.93-0.82 (m, 4H).

Example 227: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The title compound (36.4 mg, 87% yield) was prepared using analogous conditions as described in Example 43 where 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,-4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37) was used instead of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,-4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₄H₄₀N₆O₆S, 660.3; m/z found, 661.3 [M+H]⁺.

Example 228: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid isomers (Example 227) was separated by chiral SFC (Chiralpak AS-H, mobile phase: 85% CO₂, 15% MeOH with 0.1% NH₄OH) to afford two enantiomers. The first eluting isomer (44 mg) was designated (*S): ¹H NMR (500 MHz, CDCl₃) δ 8.52 (s, 1H), 8.30-8.25 (m, 1H), 8.00-7.95 (m, 1H), 7.68-7.56 (m, 2H), 7.48 (d, J=8.5 Hz, 1H), 5.04 (s, 1H), 4.52 (d, J=15.1 Hz, 1H), 4.37 (d, J=15.1 Hz, 1H), 4.05-3.91 (m, 2H), 3.80-3.73 (m, 1H), 3.65 (d, J=10.8 Hz, 1H), 3.56 (s, 1H), 3.42 (s, 2H), 2.90 (s, 3H), 2.45 (s, 3H), 2.39 (s, 3H), 1.60-1.49 (m, 2H), 1.48-1.25 (m, 12H).

Example 229: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The second eluting isomer (41 mg) from the separation of isomers by chiral SFC described in Example 228 was designated (*R): ¹H NMR (500 MHz, CDCl₃) δ 8.49 (s, 1H), 8.29-8.26 (m, 1H), 8.00-7.96 (m, 1H), 7.64-7.57 (m, 2H), 7.47 (d, J=8.6 Hz, 1H), 5.04 (s, 1H), 4.54 (d, J=15.2 Hz, 1H), 4.36 (d, J=15.0 Hz, 1H), 4.05-3.93 (m, 2H), 3.78-3.72 (m, 1H), 3.69-3.62 (m, 1H), 3.60-3.53 (m, 1H), 3.51-3.32 (m, 2H), 2.90 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 1.59-1.50 (m, 2H), 1.47-1.19 (m, 12H).

Example 230: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (82.6 mg, 97% yield) was prepared using analogous conditions as described in Example 186 where ethyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (prepared in the synthesis of Intermediate 106, Step E) was used instead of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, 8′-fluoro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 80) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide and the hydrolysis reaction was run at 50° C. MS (ESI): mass calcd. for C₃₀H₃₀FN₅O₅S, 591.2; m/z found, 592.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=3.0 Hz, 1H), 8.05-7.98 (m, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.15-7.10 (m, 1H), 7.10-7.04 (m, 2H), 6.69 (d, J=7.2 Hz, 1H), 4.91 (t, J=7.9 Hz, 1H), 4.32 (s, 2H), 3.62-3.44 (m, 2H), 3.23-3.10 (m, 1H), 3.03-2.94 (m, 1H), 2.65 (s, 3H), 2.30 (s, 3H), 2.01-1.93 (m, 1H), 1.22-1.06 (m, 6H), 0.57-0.46 (m, 2H).

Example 231: (R/S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (223 mg, 71.6% yield) was prepared using analogous conditions as described in Example 11 where (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) was used instead of (*S)-7a-methyl6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide and the title compound was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21-8.14 (m, 1H), 7.94-7.87 (m, 1H), 7.25-7.07 (m, 3H), 6.95-6.88 (m, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.63 (dt, J=8.3, 4.5 Hz, 1H), 4.89-4.75 (m, 1H), 4.43-4.21 (m, 4H), 4.21-4.06 (m, 1H), 3.99 (t, J=15.4 Hz, 1H), 3.23-2.95 (m, 3H), 2.95-2.76 (m, 1H), 2.66 (d, J=17.6 Hz, 3H), 2.00 (s, 3H), 1.64-1.04 (m, 8H), 0.60-0.46 (m, 2H), 0.46-0.31 (m, 2H).

Example 232: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of (R/S)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 231) was separated by chiral SFC (Chiralpak OZ-H, mobile phase: 60% CO₂, 40% EtOH) to afford two diastereomers. The first eluting isomer (105 mg) was designated (*S): ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=4.4 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.30-7.24 (m, 2H), 7.21-7.16 (m, 1H), 6.97-6.90 (m, 2H), 6.70 (t, J=6.0 Hz, 1H), 4.95-4.85 (m, 1H), 4.47-4.33 (m, 4H), 4.17-4.01 (m, 2H), 3.29-3.01 (m, 3H), 2.99-2.77 (m, 2H), 2.76-2.65 (m, 3H), 2.11 (s, 3H), 1.63-1.28 (m, 7H), 0.64-0.54 (m, 2H), 0.49-0.37 (m, 2H).

Example 233: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (120 mg) from the separation of isomers by chiral SFC described in Example 232 was designated (*R): ¹H NMR (400 MHz, CDCl₃) δ 8.20-8.14 (m, 1H), 7.94-7.88 (m, 1H), 7.20-7.10 (m, 3H), 6.97 (d, J=7.7 Hz, 1H), 6.84-6.78 (m, 1H), 6.63 (dd, J=7.8, 4.6 Hz, 1H), 4.87-4.79 (m, 1H), 4.40-4.10 (m, 5H), 3.96 (d, J=14.8 Hz, 1H), 1.54-1.45 (m, 2H), 3.17-3.01 (m, 3H), 2.93-2.81 (m, 1H), 2.71-2.55 (m, 4H), 2.00 (s, 3H), 1.63-1.54 (m, 1H), 1.30-1.24 (m, 3H), 1.15-1.04 (m, 1H), 0.57-0.49 (m, 2H), 0.42-0.35 (m, 2H).

Example 234: (R/S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (196 mg, 71% yield) was prepared using analogous conditions as described in Example 11 where (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3) was used instead of (*S)-7a-methyl6,7,7a,8,9,19-hexahydropyrido[2,3-f]pyrollo[2,1-d[1,2,5]thiadiazepine 5,5-dioxide and the title compound was purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH). MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J=4.9 Hz, 1H), 7.95-7.87 (m, 1H), 7.25-7.08 (m, 3H), 6.94-6.86 (m, 1H), 6.84-6.77 (m, 1H), 6.63 (dt, J=7.7, 4.1 Hz, 1H), 4.83 (t, J=7.5 Hz, 1H), 4.42-4.21 (m, 4H), 4.21-4.07 (m, 1H), 4.07-3.92 (m, 1H), 3.23-2.76 (m, 5H), 2.74-2.59 (m, 4H), 2.01 (s, 3H), 1.66-1.07 (m, 6H), 0.61-0.48 (m, 2H), 0.40 (dd, J=9.5, 5.0 Hz, 2H).

Example 235: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of (R/S)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 234) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 60% CO₂, 40% MeOH) to afford two diastereomers. The first eluting isomer (100 mg) was designated (*R): MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.25 (m, 1H), 8.05-8.00 (m, 1H), 7.37-7.28 (m, 2H), 7.14-7.07 (m, 3H), 6.80 (dd, J=7.8, 4.7 Hz, 1H), 4.97 (t, J=7.6 Hz, 1H), 4.49-4.40 (m, 4H), 4.21-4.08 (m, 2H), 3.19-2.98 (m, 5H), 2.84 (s, 3H), 2.24 (s, 3H), 1.70-1.46 (m, 3H), 1.40-1.09 (m, 4H), 0.65-0.59 (m, 2H), 0.51-0.42 (m, 2H).

Example 236: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (98 mg) from the separation of isomers by chiral SFC described in Example 235 was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₈N₆O₄S, 614.3; m/z found, 615.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.24 (m, 1H), 8.05-7.99 (m, 1H), 7.37-7.30 (m, 2H), 7.15-7.03 (m, 3H), 6.79 (s, 1H), 4.99-4.91 (m, 1H), 4.52-4.38 (m, 4H), 4.21-4.09 (m, 2H), 3.22-2.99 (m, 5H), 2.81 (s, 3H), 2.22 (s, 3H), 1.67-1.23 (m, 7H), 0.67-0.59 (m, 2H), 0.50-0.45 (m, 2H).

Example 237: (R/S)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (129 mg, 91% yield) was prepared using analogous conditions as described in Example 186 where 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate (Intermediate 108) was used instead of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and the hydrolysis reaction was run overnight. MS (ESI): mass calcd. for C₂₉H₃₁N₅O₆S, 577.2; m/z found, 578.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.99-7.87 (m, 1H), 7.67-7.57 (m, 1H), 7.50-7.42 (m, 1H), 7.42-7.27 (m, 3H), 7.24-7.17 (m, 1H), 6.85 (d, J=8.0 Hz, 1H), 5.16-5.04 (m, 1H), 4.92-4.75 (m, 3H), 4.75-4.52 (m, 3H), 4.40-4.25 (m, 1H), 4.04-3.78 (m, 2H), 3.38-3.26 (m, 1H), 2.96-2.73 (m, 4H), 2.43 (s, 3H), 1.69-1.52 (m, 3H), 1.52-1.43 (m, 1H).

Example 238: (*S)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(6-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 237) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting isomer (50 mg) was designated (*S): MS (ESI): mass calcd. for C₂₉H₃₁N₅O₆S, 577.2; m/z found, 578.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (dd, J=7.8, 1.7 Hz, 1H), 7.63-7.59 (m, 1H), 7.47-7.44 (m, 1H), 7.39-7.32 (m, 2H), 7.31-7.28 (m, 1H), 7.20-7.15 (m, 1H), 6.85-6.82 (m, 1H), 5.09-5.03 (m, 1H), 4.91-4.79 (m, 4H), 4.68-4.59 (m, 3H), 4.34-4.28 (m, 1H), 4.00-3.92 (m, 1H), 3.88-3.82 (m, 1H), 3.30-3.21 (m, 1H), 2.86 (d, J=12.1 Hz, 1H), 2.79 (s, 3H), 2.44 (s, 3H), 1.62-1.57 (m, 3H).

Example 239: (*R)-3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (48 mg) from the separation of isomers by chiral SFC described in Example 238 was designated (*R): MS (ESI): mass calcd. for C₂₉H₃₁N₅O₆S, 577.2; m/z found, 578.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.91 (dd, J=7.8, 1.6 Hz, 1H), 7.63-7.58 (m, 1H), 7.47-7.43 (m, 1H), 7.38-7.31 (m, 2H), 7.30-7.28 (m, 1H), 7.22-7.18 (m, 1H), 6.85 (d, J=7.9 Hz, 1H), 5.10-5.04 (m, 1H), 4.91-4.77 (m, 4H), 4.69-4.57 (m, 3H), 4.33-4.28 (m, 1H), 3.98-3.91 (m, 1H), 3.87-3.81 (m, 1H), 3.31-3.24 (m, 1H), 2.89-2.82 (m, 1H), 2.79 (s, 3H), 2.43 (s, 3H), 1.62-1.57 (m, 3H).

Example 240: (R/S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (118 mg, 85% yield) was prepared using analogous conditions as described in Example 186 where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate (Intermediate 108) was used instead of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and the hydrolysis reaction was run overnight. MS (ESI): mass calcd. for C₂₈H₃₀N₆O₆S, 578.2; m/z found, 579.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.63-8.51 (m, 1H), 8.31-8.17 (m, 1H), 7.70-7.43 (m, 1H), 7.41-7.28 (m, 2H), 7.20 (d, J=8.7 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 5.17-5.03 (m, 1H), 5.03-4.88 (m, 2H), 4.88-4.76 (m, 2H), 4.76-4.61 (m, 3H), 4.41-4.34 (m, 1H), 4.18-3.91 (m, 2H), 3.37-3.26 (m, 1H), 2.97-2.77 (m, 4H), 2.42 (s, 3H), 1.64-1.55 (m, 3H).

Example 241: (*S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 240) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting isomer (42 mg) was designated (*S): MS (ESI): mass calcd. for C₂₈H₃₀N₆O₆S, 578.2; m/z found, 579.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.61-8.56 (m, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.30-7.27 (m, 1H), 7.25-7.18 (m, 1H), 6.94-6.85 (m, 1H), 5.15-5.00 (m, 1H), 5.00-4.75 (m, 4H), 4.70-4.59 (m, 3H), 4.39-4.31 (m, 1H), 4.10-4.00 (m, 1H), 4.00-3.90 (m, 1H), 3.36-3.23 (m, 1H), 2.88-2.76 (m, 4H), 2.40 (s, 3H), 1.63-1.55 (m, 3H).

Example 242: (*R)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (44 mg) from the separation of isomers by chiral SFC described in Example 241 was designated (*R): MS (ESI): mass calcd. for C₂₈H₃₀N₆O₆S, 578.2; m/z found, 579.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.61-8.54 (m, 1H), 8.29-8.23 (m, 1H), 7.41-7.33 (m, 2H), 7.30-7.27 (m, 1H), 7.23-7.16 (m, 1H), 6.92-6.84 (m, 1H), 5.13-5.01 (m, 1H), 4.94-4.74 (m, 4H), 4.69-4.60 (m, 3H), 4.36-4.26 (m, 1H), 4.06-3.90 (m, 2H), 3.33-3.25 (m, 1H), 2.85-2.76 (m, 4H), 2.42-2.38 (m, 3H), 1.62-1.55 (m, 3H).

Example 243: (R/S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (63 mg, 33% yield) was prepared using analogous conditions as described in Example 186 where 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 5) was used instead of (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide, ethyl 3-((1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate (Intermediate 108) was used instead of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoateate and the hydrolysis reaction was run overnight. MS (ESI): mass calcd. for C₂₈H₃₀N₆O₅S, 562.2; m/z found, 563.2 [M+H]⁺.

Example 244: (*S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of (R/S)-3-(6-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 243) was separated by chiral SFC (Chiralpak AD-H, mobile phase: 80% CO₂, 20% EtOH) to afford two enantiomers. The first eluting isomer (29 mg) was designated (*S): ¹H NMR (500 MHz, CDCl₃) δ 8.47 (dd, J=4.9, 2.0 Hz, 1H), 8.31 (dd, J=7.6, 2.0 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.32 (dd, J=7.6, 4.9 Hz, 1H), 7.26-7.21 (m, 2H), 7.01 (d, J=7.9 Hz, 1H), 4.99 (t, J=7.4 Hz, 1H), 4.62 (q, J=7.3 Hz, 2H), 4.51-4.37 (m, 2H), 3.73-3.53 (m, 2H), 3.30-3.23 (m, 1H), 2.91-2.83 (m, 4H), 2.62-2.56 (m, 2H), 2.41-2.39 (m, 3H), 1.24-1.11 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 245: (*R)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (28 mg) from the separation of isomers by chiral SFC described in Example 244 was designated (*R): ¹H NMR (500 MHz, CDCl₃) δ 8.47 (dd, J=4.9, 2.0 Hz, 1H), 8.31 (dd, J=7.6, 1.9 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.32 (dd, J=7.6, 4.9 Hz, 1H), 7.30-7.21 (m, 2H), 7.02 (d, J=7.9 Hz, 1H), 4.99 (t, J=7.5 Hz, 1H), 4.62 (q, J=7.3 Hz, 2H), 4.50-4.36 (m, 2H), 3.71-3.52 (m, 2H), 3.28-3.20 (m, 1H), 2.90-2.82 (m, 4H), 2.62-2.55 (m, 2H), 2.40 (s, 3H), 1.23-1.11 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

Example 246: 3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetic acid salt

To a solution of methyl 3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 1, Step B, 112 mg, 0.276 mmol) in THF (4.5 mL) was added sequentially (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 99.2 mg, 0.414 mmol), triphenylphosphine polystyrene resin (184 mg, 3 mmol/g, 0.552 mmol), and DIAD (0.108 mL, 0.553 mmol). The reaction mixture was stirred at room temperature under air for 18 hours. A second portion of triphenylphosphine polystyrene resin and DIAD (same amounts as above) was added and the reaction mixture was stirred at room temperature for 3 hours. A third portion of triphenylphosphine polystyrene resin and DIAD (same amounts as above) was added and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of MeOH (4 mL) and aqueous NaOH solution (1.0 M, 0.83 mL, 0.83 mmol). The reaction mixture was then heated in an oil bath at 90° C. for 80 minutes. The pH of the reaction mixture was adjusted to pH 3 with 1 N aqueous HCl and then the reaction mixture was concentrated. The residue was purified by preparative HPLC (10-90% CH₃CN—H₂O, 0.1% TFA) to afford the title compound and its trifluoroacetic acid salt (72 mg). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.42-8.27 (m, 1H), 8.24 (td, J=5.8, 2.2, Hz, 1H), 7.67 (s, 1H), 7.16-6.90 (m, 5H), 6.88-6.46 (m, 1H), 5.04-4.85 (m, 1H), 4.64-4.41 (m, 6H), 3.83-3.64 (m, 2H), 3.44 (ddd, J=15.9, 12.6, 3.8 Hz, 1H), 3.14-2.93 (m, 3H), 2.28 (d, J=9.1 Hz, 3H), 2.18-1.96 (m, 2H), 1.94-1.58 (m, 2H).

Example 247: (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6 (7H)-yl)methyl)-4-methylphenyl)propanoic acid trifluoroacetate isomers (Example 246, 67 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm, 250×20 mm, mobile phase: 70% CO₂, 30% EtOH) to afford two diastereoisomers. The first eluting isomer (20 mg, 36%) was designated (*S): MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.3 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.27 (dd, J=4.8, 1.8 Hz, 1H), 8.04 (dd, J=7.6, 2.0 Hz, 1H), 7.74 (s, 1H), 7.27-6.84 (m, 6H), 4.64 (t, J=7.8 Hz, 1H), 4.50-4.41 (m, 4H), 4.39-4.31 (m, 1H), 4.25-4.17 (m, 1H), 3.61 (dt, J=10.9, 5.6 Hz, 1H), 3.54-3.49 (m, 1H), 3.23-3.03 (m, 3H), 2.92 (t, J=12.9 Hz, 1H), 2.27 (s, 3H), 2.04-1.90 (m, 1H), 1.81-1.70 (m, 1H), 1.69-1.55 (m, 1H), 1.52-1.43 (m, 1H).

Example 248: (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (22 mg, 39%) from the separation by chiral SFC described in Example 247 was designated (*R): MS (ESI): mass calcd. C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.3 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.27 (dd, J=4.8, 1.8 Hz, 1H), 8.05 (dd, J=7.6, 2.0 Hz, 1H), 7.72 (s, 1H), 7.26-6.83 (m, 6H), 4.65 (t, J=8.1 Hz, 1H), 4.48-4.40 (m, 4H), 4.39-4.33 (m, 1H), 4.26-4.18 (m, 1H), 3.68-3.58 (m, 1H), 3.57-3.50 (m, 1H), 3.17 (dd, J=13.6, 3.5 Hz, 1H), 3.11 (d, J=8.1 Hz, 2H), 2.99-2.89 (m, 1H), 2.27 (s, 3H), 2.01-1.88 (m, 1H), 1.84-1.73 (m, 1H), 1.72-1.56 (m, 1H), 1.50-1.39 (m, 1H).

Example 249: 3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetic acid salt

(R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91, 75.3 mg, 0.330 mmol) was dissolved in DMF (0.75 mL). The solution was cooled in an ice bath and NaH (60% dispersion in mineral oil, 39.6 mg, 0.990 mmol) was added. The mixture was stirred in the ice bath for 10 minutes. A solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate in DMF (Example 1, Step C, 1.0 mL, 0.30 M, 0.30 mmol) was added. The reaction mixture was stirred in the ice bath for 40 minutes. An aqueous solution of NaOH (0.60 mL, 1.0 M, 0.60 mmol) was added and the mixture was heated in an oil bath at 60° C. for 30 minutes. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by preparative HPLC (10-90% CH₃CN—H₂O, 0.1% TFA) to afford the title compound and its trifluoroacetic acid salt (94.6 mg) as a white powder. MS (ESI): mass calcd. for C₂₄H₂₉F₂N₅O₆S, 601.2; m/z found, 602.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (dd, J=4.6, 2.0 Hz, 1H), 8.25 (dd, J=7.8, 1.8 Hz, 1H), 7.74 (d, J=1.0 Hz, 1H), 7.30-7.24 (m, 1H), 7.18-7.09 (m, 3H), 6.99 (s, 1H), 6.69 (t, J=72.8 Hz, 1H), 4.68-4.61 (m, 1H), 4.48-4.37 (m, 5H), 4.05 (dd, J=14.4, 1.3 Hz, 1H), 3.62-3.52 (m, 1H), 3.18-3.06 (m, 3H), 2.31 (s, 3H), 1.75-1.61 (m, 1H), 1.55-1.40 (m, 1H), 0.99 (t, J=7.3 Hz, 3H).

Example 250: (*S)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetic acid salt (Example 249, 92 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×20 mm, mobile phase: 80% CO₂, 20% MeOH) to afford two diastereoisomers. The first eluting isomer (36 mg, 44%) was designated (*S): MS (ESI): mass calcd. for C₂₄H₂₉F₂N₅O₆S, 601.2; m/z found, 602.2 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.46 (br s, 1H), 8.29 (dd, J=7.8, 1.8 Hz, 1H), 7.71 (s, 1H), 7.41 (dd, J=7.6, 5.1, Hz, 1H), 7.30-7.24 (m, 1H), 7.24-6.86 (m, 4H), 4.64 (t, J=7.6 Hz, 1H), 4.58 (d, J=13.6 Hz, 1H), 4.41 (s, 3H), 4.32-4.22 (m, 1H), 3.94 (d, J=13.6 Hz, 1H), 3.68 (dd, J=15.4, 10.4 Hz, 1H), 3.16-3.06 (m, 2H), 2.98-2.89 (m, 1H), 2.33 (s, 3H), 1.62-1.49 (m, 1H), 1.41-1.24 (m, 1H), 0.90 (t, J=7.3 Hz, 3H).

Example 251: (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (34 mg, 42%) from the mixture that was separated by chiral SFC described in Example 250 was designated (*R): MS (ESI): mass calcd. for C₂₄H₂₉F₂N₅O₆S, 601.2; m/z found, 602.3 [M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.46 (br s, 1H), 8.29 (dd, J=7.6, 2.0 Hz, 1H), 7.74 (s, 1H), 7.41 (dd, J=7.6, 5.1, Hz, 1H), 7.28-7.24 (m, 1H), 7.24-6.85 (m, 4H), 4.64 (br t, J=7.6 Hz, 1H), 4.56 (d, J=14.2 Hz, 1H), 4.42 (s, 3H), 4.28-4.19 (m, 1H), 3.94 (d, J=14.2 Hz, 1H), 3.67 (dd, J=15.4, 10.4, Hz, 1H), 3.20-3.00 (m, 2H), 2.93 (d, J=14.2 Hz, 1H), 2.32 (s, 3H), 1.60-1.48 (m, 1H), 1.36-1.23 (m, 1H), 0.89 (t, J=7.3 Hz, 3H).

Example 252: 3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

DMF (1.1 mL) was added to mixture of 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59, 71 mg, 0.29 mmol) and sodium hydride (60% dispersion in mineral oil, 13 mg, 0.33 mmol) which had been cooled to 0° C. After 10 minutes, a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate (Intermediate 31, 90 mg, 0.23 mmol) in DMF (0.45 mL) was added and the mixture was allowed to warm to room temperature. After 2 hours, additional sodium hydride (15 mg) was added and the mixture allowed to stir overnight. The mixture was filtered and the filtrate was purified by reverse phase HPLC (acetonitrile-water containing 0.05% NH₄OH) to provide the title compound (14 mg, 11%). MS (ESI): mass calcd. for C₂₉H₃₁N₅O₆S, 577.2; m/z found, 578.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63-8.58 (m, 1H), 8.22 (dd, J=7.6, 1.9 Hz, 1H), 7.54-7.47 (m, 2H), 7.38 (d, J=8.7 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.10-7.02 (m, 2H), 4.90-4.80 (m, 1H), 4.70-4.60 (m, 2H), 4.46-4.35 (m, 4H), 4.25 (s, 2H), 3.79 (s, 2H), 2.71 (s, 3H), 2.58-2.54 (m, 2H), 2.17 (s, 3H), 1.49-1.42 (m, 3H).

Example 253: 3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (E)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. A mixture containing 7-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 110, 441 mg, 1.66 mmol), sodium acetate (372 mg, 4.54 mmol), Herrmann's catalyst (172 mg, 0.183 mmol), ethyl acrylate (0.8 mL, 7.4 mmol), and DMA (7 mL) was placed in a sealed tube and heated at 150° C. in a microwave reactor. After 1 hour, the mixture was cooled to room temperature. Ethyl acetate was added and the mixture was filtered through diatomaceous earth. Hexanes were added and the organic solution was washed sequentially with water and brine. The organic layer was dried over MgSO₄, filtered, and combined with the organic layer from a separate, small-scale reaction starting with 55 mg of 7-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine. The combined organic layers were absorbed onto diatomaceous earth for purification by flash column chromatography (hexanes-ethyl acetate) to afford the title compound (407 mg, 77%). MS (ESI): mass calcd. for C₁₂H₁₀F₃N₃O₂, 285.1; m/z found, 286.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=7.3 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J=16.0 Hz, 1H), 7.26-7.20 (m, 1H), 6.58 (d, J=16.0 Hz, 1H), 4.36-4.28 (m, 2H), 1.41-1.33 (m, 3H).

Step B: Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Triethylamine (0.35 mL, 2.5 mmol) and [Rh(COD)Cl]₂ (55 mg, 0.11 mmol) were added sequentially to a slurry of ethyl (E)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (283 mg, 0.992 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (Intermediate 20, 583 mg, 2.01 mmol) in 1,4-dioxane (3 mL) and water (1.5 mL). The reaction vessel was heated to 95° C. After 45 minutes, ethyl acetate, hexanes, and half-saturated aqueous sodium chloride solution were added. The biphasic mixture was separated. The organic layer was dried over Na₂SO₄, filtered, and combined with the organic layer from a separate, small-scale reaction starting with 100 mg of ethyl (E)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate. Diatomaceous earth was added and the slurry was concentrated to dryness under reduced pressure. The solids were purified by flash column chromatography (hexanes-ethyl acetate) to afford the title compound (408 mg) which was used without further purification. MS (ESI): mass calcd. for C₂₂H₂₂F₃N₃O₄, 449.2; m/z found, 450.1 [M+H]⁺.

Step C: Ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Potassium carbonate (304 mg, 2.2 mmol) was added to a solution of ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (390 mg, 0.868 mmol) in ethanol (7 mL) at room temperature. After 18 hours, the mixture was partioned between ethyl acetate, hexanes, and water. The layers were separated and the organic layer was washed with brine, dried over Na₂SO₄, filtered, and then absorbed onto diatomaceous earth. Purification by flash column chromatography (hexanes-ethyl acetate) provided the title compound (219 mg, 62%) as a yellow foam. MS (ESI): mass calcd. for C₂₀H₂₀F₃N₃O₃, 407.1; m/z found, 408.1 [M+H]⁺.

Step D: Ethyl 3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.0725 mL, 0.363 mmol) was added to a mixture of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (100 mg, 0.245 mmol), (5)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 75, 89 mg, 0.37 mmol), and triphenyl phosphine (123 mg, 0.368 mmol) in THF (1 mL) at room temperature. After 2 hours, additional diisopropyl azodicarboxylate (0.0725 mL) and triphenyl phosphine (100 mg) were added. After 20 minutes, the mixture was filtered through diatomaceous earth and then the filtrate was absorbed onto diatomaceous earth. Purification by flash column chromatography (hexanes-ethyl acetate) provided the title compound (137 mg, 89%). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺.

Step E: 3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (137 mg, 0.218 mmol), 1 M aqueous NaOH solution (0.44 mL, 0.44 mmol), and THF (1 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH of the reaction mixture was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure, and purified by reverse phase HPLC (acetonitrile-water containing 0.05% NH₄OH). The pure fractions resulting from the preparative basic HPLC were collected, concentrated under reduced pressure, adjusted to pH 3-4 with 1 M aqueous HCl solution, and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound (47 mg, 36% yield). MS (ESI): mass calcd. for C₂₈H₂₇F₃N₆O₄S, 600.2; m/z found, 601.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.51 (d, J=7.1 Hz, 1H), 8.38-8.32 (m, 1H), 8.05-7.97 (m, 2H), 7.35-7.24 (m, 2H), 7.19-7.13 (m, 2H), 6.97-6.87 (m, 1H), 4.61-4.52 (m, 1H), 4.37-4.13 (m, 3H), 3.68-3.56 (m, 1H), 3.56-3.45 (m, 1H), 3.27-2.88 (m, 4H), 2.23 (s, 3H), 2.02-1.82 (m, 1H), 1.76-1.55 (m, 2H), 1.42 (s, 1H).

Example 254: (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 253, 47 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×20 mm, mobile phase: 60% CO₂, 40% iPrOH) to afford two diastereoisomers. The first eluting isomer (18 mg) was designated (*S). MS: mass calcd. for C₂₈H₂₇F₃N₆O₄S, 600.2; m/z found, 600.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=7.1 Hz, 1H), 8.37-8.32 (m, 1H), 8.01 (dd, J=7.7, 1.8 Hz, 1H), 7.98 (s, 1H), 7.33-7.25 (m, 2H), 7.18-7.12 (m, 2H), 6.92 (dd, J=7.8, 4.7 Hz, 1H), 4.61-4.53 (m, 1H), 4.35-4.15 (m, 3H), 3.69-3.57 (m, 1H), 3.57-3.47 (m, 1H), 3.21-2.92 (m, 4H), 2.22 (s, 3H), 1.94-1.81 (m, 1H), 1.78-1.66 (m, 2H), 1.41 (s, 1H).

Example 255: (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (20 mg) from the chiral separation described in Example 254 was designated (*R). MS: mass calcd. for C₂₄H₂₇F₃N₆O₄S, 600.2; m/z found, 600.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=7.2 Hz, 1H), 8.35 (dd, J=4.7, 1.8 Hz, 1H), 8.01 (dd, J=7.8, 1.8 Hz, 1H), 7.98 (s, 1H), 7.33-7.27 (m, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.16-7.12 (m, 2H), 6.92 (dd, J=7.8, 4.7 Hz, 1H), 4.60-4.51 (m, 1H), 4.37-4.22 (m, 2H), 4.20-4.11 (m, 1H), 3.66-3.54 (m, 1H), 3.50 (s, 1H), 3.19-3.07 (m, 2H), 3.04-2.87 (m, 2H), 2.22 (s, 3H), 2.00-1.89 (m, 1H), 1.70-1.55 (m, 2H), 1.47-1.37 (m, 1H).

Example 256: 3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (118 mg, 77%) was prepared using analogous conditions as described in Example 253 where (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91) was used instead of (S)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide in Step D. MS (ESI): mass calcd. for C₂₇H₂₆F₃N₅O₅S, 589.2; m/z found, 590.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (s, 1H), 8.58-8.53 (m, 1H), 8.52-8.47 (m, 1H), 8.26-8.21 (m, 1H), 7.99-7.94 (m, 1H), 7.47 (dd, J=7.6, 4.9 Hz, 1H), 7.36-7.28 (m, 2H), 7.20-7.12 (m, 2H), 4.59-4.50 (m, 1H), 4.45 (d, J=13.9 Hz, 1H), 4.39-4.23 (m, 1H), 3.93-3.83 (m, 1H), 3.73-3.61 (m, 1H), 3.25-3.12 (m, 1H), 3.12-2.98 (m, 1H), 2.89-2.73 (m, 1H), 2.26 (s, 3H), 1.60-1.31 (m, 2H), 0.96-0.88 (m, 3H).

Example 257: (*S)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 256) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×20 mm, mobile phase: 60% CO₂, 40% MeOH) to afford two diastereoisomers. The first eluting isomer (47 mg) was designated (*S). MS: mass calcd. for C₂₇H₂₆F₃N₅O₅S, 589.2; m/z found, 589.2 [M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (dd, J=4.8, 1.9 Hz, 1H), 8.49 (d, J=7.1 Hz, 1H), 8.26-8.21 (m, 1H), 7.94 (s, 1H), 7.46 (dd, J=7.6, 4.8 Hz, 1H), 7.35-7.28 (m, 2H), 7.19-7.11 (m, 2H), 4.59-4.50 (m, 1H), 4.45 (d, J=13.9 Hz, 1H), 4.40-4.29 (m, 1H), 3.89 (d, J=13.9 Hz, 1H), 3.73-3.61 (m, 1H), 3.18-3.05 (m, 1H), 3.05-2.95 (m, 1H), 2.86 (d, J=15.3 Hz, 1H), 2.26 (s, 3H), 1.59-1.47 (m, 1H), 1.43-1.32 (m, 1H), 0.97-0.87 (m, 3H).

Example 258: (*R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (47 mg) from the chiral separation described in Example 257 was designated (*R). MS: mass calcd. for C₂₇H₂₆F₃N₅O₅S, 589.2; m/z found, 589.2[M]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57-8.53 (m, 1H), 8.48 (d, J=7.1 Hz, 1H), 8.25-8.21 (m, 1H), 7.93 (s, 1H), 7.49-7.43 (m, 1H), 7.34-7.29 (m, 1H), 7.27 (s, 1H), 7.18-7.10 (m, 2H), 4.58-4.49 (m, 1H), 4.45 (d, J=13.9 Hz, 1H), 4.33-4.23 (m, 1H), 3.88 (d, J=13.9 Hz, 1H), 3.72-3.60 (m, 1H), 3.17-3.05 (m, 1H), 2.93 (s, 1H), 2.78 (d, J=15.3 Hz, 1H), 2.26 (s, 3H), 1.49-1.37 (m, 1H), 1.27-1.13 (m, 1H), 0.85-0.76 (m, 3H).

Example 259: 3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (86 mg) was prepared using analogous conditions as described in Example 7 using 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.2; m/z found, 618.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63-8.57 (m, 1H), 8.33 (d, J=7.1 Hz, 1H), 8.24-8.19 (m, 1H), 7.53-7.48 (m, 1H), 7.23-7.16 (m, 2H), 7.14-7.08 (m, 2H), 4.88-4.80 (m, 1H), 4.44-4.20 (m, 6H), 3.84-3.72 (m, 2H), 2.77-2.69 (m, 5H), 2.20 (s, 3H).

Example 260: (*S)-3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 259, 80 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×20 mm, Mobile phase: 65% CO₂, 30% iPrOH) to afford two enantiomers. The first eluting isomer (37 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.2; m/z found, 618.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (dd, J=4.9, 1.9 Hz, 1H), 8.36 (d, J=7.2 Hz, 1H), 8.24-8.20 (m, 1H), 7.53-7.48 (m, 1H), 7.28-7.21 (m, 2H), 7.18-7.13 (m, 2H), 4.88-4.79 (m, 1H), 4.45-4.22 (m, 6H), 3.85-3.71 (m, 2H), 3.02 (d, J=7.5 Hz, 2H), 2.72 (s, 3H), 2.20 (s, 3H).

Example 261: (*R)-3-(3-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (39 mg) from the chiral separation described in Example 260 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.2; m/z found, 618.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62-8.58 (m, 1H), 8.32 (d, J=7.1 Hz, 1H), 8.22 (dd, J=7.7, 1.9 Hz, 1H), 7.50 (dd, J=7.6, 4.8 Hz, 1H), 7.21-7.15 (m, 2H), 7.13-7.08 (m, 2H), 4.86-4.79 (m, 1H), 4.44-4.20 (m, 6H), 3.84-3.72 (m, 2H), 2.72-2.69 (m, 5H), 2.19 (s, 3H).

Example 262: (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (49 mg) was prepared using analogous conditions as described in Example 7 using (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 13) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and the following chiral SFC separation conditions in Step B: stationary phase: Chiralpak AD-H 5 μm 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH. The title compound was the first eluting isomer and designated (*S; *S). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₅S, 630.2; m/z found, 631.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41-8.33 (m, 2H), 8.05-8.00 (m, 1H), 7.29-7.24 (m, 1H), 7.24-7.11 (m, 3H), 7.01-6.95 (m, 1H), 4.84-4.74 (m, 1H), 4.36-4.21 (m, 3H), 4.21-4.11 (m, 1H), 3.84-3.75 (m, 1H), 3.66-3.55 (m, 2H), 3.53-3.39 (m, 2H), 3.31-3.24 (m, 1H), 3.24-3.13 (m, 1H), 3.09-2.96 (m, 2H), 2.70 (s, 3H), 2.15 (s, 3H).

Example 263: (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (45 mg) from the chiral separation described in Example 262 was designated (*R, *S). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₅S, 630.2; m/z found, 631.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38-8.32 (m, 2H), 8.05-7.99 (m, 1H), 7.29-7.20 (m, 2H), 7.18-7.07 (m, 2H), 7.00-6.94 (m, 1H), 4.91-4.80 (m, 1H), 4.39-4.28 (m, 2H), 4.25-4.05 (m, 2H), 3.62-3.41 (m, 4H), 3.24-3.08 (m, 3H), 3.01-2.84 (m, 2H), 2.74 (s, 3H), 2.13 (s, 3H).

Example 264: 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (92 mg) was prepared using analogous conditions as described in Example 7 using (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄S, 614.2; m/z found, 615.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.44-8.37 (m, 1H), 8.37-8.31 (m, 1H), 8.04-7.97 (m, 1H), 7.32-7.23 (m, 1H), 7.23-7.12 (m, 3H), 6.95-6.88 (m, 1H), 4.88-4.76 (m, 1H), 4.41-4.12 (m, 3H), 3.67-3.54 (m, 1H), 3.54-3.43 (m, 1H), 3.18-2.86 (m, 4H), 2.78-2.69 (m, 3H), 2.26-2.19 (m, 3H), 1.97-1.79 (m, 1H), 1.75-1.54 (m, 2H), 1.48-1.36 (m, 1H).

Example 265: 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (109 mg) was prepared using analogous conditions as described in Example 7 using (R)-6,7,7a,8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 83) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₄S, 613.2; m/z found, 614.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.34 (s, 1H), 8.41 (t, J=6.4 Hz, 1H), 7.77-7.66 (m, 1H), 7.51-7.41 (m, 1H), 7.30-7.24 (m, 1H), 7.22-7.12 (m, 3H), 7.07-6.93 (m, 2H), 4.89-4.76 (m, 1H), 4.27-3.88 (m, 3H), 3.27 (s, 2H), 3.17-3.04 (m, 2H), 3.04-2.80 (m, 2H), 2.78-2.70 (m, 3H), 2.28-2.19 (m, 3H), 1.98-1.52 (m, 3H), 1.36 (s, 1H).

Example 266: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 265, 98 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×20 mm, mobile phase: 60% CO₂, 40% iPrOH) to afford two diastereoisomers. The first eluting isomer (39 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₄S, 613.2; m/z found, 614.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.40 (d, J=7.1 Hz, 1H), 7.75-7.67 (m, 1H), 7.49-7.40 (m, 1H), 7.29-7.23 (m, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.18-7.11 (m, 2H), 7.05-6.92 (m, 2H), 4.83 (t, J=7.8 Hz, 1H), 4.25-3.99 (m, 3H), 3.30-3.22 (m, 2H), 3.15-3.03 (m, 2H), 3.03 -2.93 (m, 1H), 2.85 (s, 1H), 2.75 (s, 3H), 2.23 (s, 3H), 2.01-1.85 (m, 1H), 1.75-1.53 (m, 2H), 1.40-1.32 (m, 1H).

Example 267: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (38 mg) from the chiral separation described in Example 266 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₄S, 613.2; m/z found, 614.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.41 (d, J=7.2 Hz, 1H), 7.76-7.69 (m, 1H), 7.49-7.42 (m, 1H), 7.30-7.24 (m, 1H), 7.21-7.13 (m, 3H), 7.04 (d, J=8.4 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 4.85-4.75 (m, 1H), 4.27-4.15 (m, 1H), 4.15-4.05 (m, 1H), 4.05-3.86 (m, 1H), 3.31-3.23 (m, 2H), 3.13-3.05 (m, 2H), 3.00-2.85 (m, 2H), 2.72 (s, 3H), 2.24 (s, 3H), 1.91-1.63 (m, 3H), 1.40-1.30 (m, 1H).

Example 268: 3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (118 mg) was prepared using analogous conditions as described in Example 7 using 4,4-dimethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 82) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₂₄H₂₈F₃N₅O₅S, 603.2; m/z found, 604.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.52-8.46 (m, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.16-8.11 (m, 1H), 7.41 (dd, J=7.6, 4.9 Hz, 1H), 7.29-7.17 (m, 3H), 7.13 (d, J=7.7 Hz, 1H), 4.90-4.81 (m, 1H), 4.49-4.34 (m, 2H), 3.68-3.40 (m, 2H), 3.20-3.08 (m, 2H), 2.75 (s, 3H), 2.16 (s, 3H), 1.14-1.05 (m, 6H).

Example 269: (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 268, 100 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×20 mm, mobile phase: 60% CO₂, 40% EtOH) to afford two diastereoisomers. The first eluting isomer (49 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₈F₃N₅O₅S, 603.2; m/z found, 604.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.50-8.47 (m, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.16-8.11 (m, 1H), 7.43-7.38 (m, 1H), 7.27-7.17 (m, 3H), 7.13 (d, J=7.7 Hz, 1H), 4.89-4.81 (m, 1H), 4.49-4.34 (m, 2H), 3.65-3.41 (m, 2H), 3.19-3.06 (m, 2H), 2.74 (s, 3H), 2.15 (s, 3H), 1.18-1.04 (m, 6H).

Example 270: (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (48 mg) from the chiral separation described in Example 269 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₈F₃N₅O₅S, 603.2; m/z found, 604.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.37 (s, 1H), 8.51-8.46 (m, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.15-8.10 (m, 1H), 7.41 (dd, J=7.6, 4.9 Hz, 1H), 7.28-7.17 (m, 3H), 7.13 (d, J=7.7 Hz, 1H), 4.89-4.81 (m, 1H), 4.48-4.34 (m, 2H), 3.65-3.42 (m, 2H), 3.17-3.08 (m, 2H), 2.74 (s, 3H), 2.15 (s, 3H), 1.18-1.03 (m, 6H).

Example 271: 3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (139 mg) was prepared using analogous conditions as described in Example 7 using (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.45-8.38 (m, 1H), 8.33-8.29 (m, 1H), 8.00-7.96 (m, 1H), 7.33-7.27 (m, 1H), 7.24-7.14 (m, 3H), 6.94-6.89 (m, 1H), 4.88-4.78 (m, 1H), 4.37-4.12 (m, 3H), 4.10-4.00 (m, 1H), 3.29-3.02 (m, 5H), 2.78-2.69 (m, 3H), 2.19-2.12 (m, 3H), 1.61-1.18 (m, 6H).

Example 272: (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 271, 121 mg) was separated by chiral SFC (stationary phase: IA 2×15 cm, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereoisomers. The first eluting isomer (56 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.41 (d, J=7.5 Hz, 1H), 8.35-8.29 (m, 1H), 8.02-7.95 (m, 1H), 7.34-7.13 (m, 4H), 6.96-6.89 (m, 1H), 4.92-4.80 (m, 1H), 4.40-4.23 (m, 2H), 4.23-4.01 (m, 2H), 3.25-3.00 (m, 5H), 2.76 (s, 3H), 2.17 (s, 3H), 1.58-1.03 (m, 6H).

Example 273: (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (55 mg) from the chiral separation described in Example 272 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=7.0 Hz, 1H), 8.34-8.28 (m, 1H), 7.98 (dd, J=7.9, 1.8 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.24-7.17 (m, 2H), 7.15 (d, J=7.7 Hz, 1H), 6.94-6.89 (m, 1H), 4.88-4.76 (m, 1H), 4.31-4.15 (m, 3H), 4.09-3.99 (m, 1H), 3.30-3.19 (m, 1H), 3.14-2.99 (m, 4H), 2.72 (s, 3H), 2.14 (s, 3H), 1.60-1.18 (m, 6H).

Example 274: (*S)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (63 mg) was prepared using analogous conditions as described in Example 7 using (S)-6,7,7a,8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 84) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and using an chiral SFC with an isocratic mobile phase of 60% CO₂ and 40% MeOH. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₄S, 613.2; m/z found, 614.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.40 (d, J=7.1 Hz, 1H), 7.72 (dd, J=7.9, 1.8 Hz, 1H), 7.49-7.43 (m, 1H), 7.29-7.24 (m, 1H), 7.21-7.13 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 4.86-4.76 (m, 1H), 4.26-3.88 (m, 3H), 3.29-3.22 (m, 2H coincident with water), 3.14-3.03 (m, 2H), 3.01-2.87 (m, 2H), 2.72 (s, 3H), 2.24 (s, 3H), 1.90-1.63 (m, 3H), 1.40-1.32 (m, 1H).

Example 275: (*R)-3-(3-(((S)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (62 mg) from the chiral separation described in Example 274 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₄S, 613.2; m/z found, 614.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (d, J=7.1 Hz, 1H), 7.71 (dd, J=7.9, 1.6 Hz, 1H), 7.48-7.42 (m, 1H), 7.28-7.23 (m, 1H), 7.22-7.11 (m, 3H), 7.03-6.93 (m, 2H), 4.87-4.80 (m, 1H), 4.23-3.99 (m, 3H), 3.29-3.24 (m, 2H), 3.13-2.94 (m, 3H), 2.91-2.80 (m, 1H), 2.75 (s, 3H), 2.23 (s, 3H), 1.98-1.87 (m, 1H), 1.73-1.53 (m, 2H), 1.40-1.33 (m, 1H).

Example 276: (*S)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (42 mg) was prepared using analogous conditions as described in Example 7 using (*R)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 14) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and the following chiral SFC conditions in Step B: stationary phase: Daicel Chiralpak AD-H 5 μm 250×20 mm, mobile phase: 50% CO₂, 50% EtOH) to afford two enantiomers. The first eluting isomer was designated (*S): MS(ESI): mass calcd. for C₂₉H₂₉F₃N₆O₅S, 630.2; m/z found, 631.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.41-8.31 (m, 2H), 8.06-7.99 (m, 1H), 7.33-7.23 (m, 2H), 7.20-7.11 (m, 2H), 7.02-6.94 (m, 1H), 4.90-4.79 (m, 1H), 4.39-4.27 (m, 2H), 4.26-4.17 (m, 1H), 4.15-4.04 (m, 1H), 3.62-3.39 (m, 5H), 3.26-3.06 (m, 4H), 2.76 (s, 3H), 2.14 (s, 3H).

Example 277: (*R)-3-(3-(((*R)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (62 mg) from the chiral separation described in Example 276 was designated (*R). MS(ESI): mass calcd. for C₂₉H₂₉F₃N₆O₅S, 630.2; m/z found, 631.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.42-8.32 (m, 2H), 8.05-7.98 (m, 1H), 7.31-7.12 (m, 4H), 7.01-6.94 (m, 1H), 4.83-4.75 (m, 1H), 4.36-4.21 (m, 3H), 4.20-4.10 (m, 1H), 3.84-3.75 (m, 1H), 3.65-3.54 (m, 2H), 3.53-3.38 (m, 2H), 3.29-3.05 (m, 4H), 2.70 (s, 3H), 2.15 (s, 3H).

Example 278: 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A mixture of ethyl (E)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)acrylate (Intermediate 112, 248 mg, 0.956 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (Intermediate 20, 834 mg, 2.87 mmol), 1 M aqueous potassium hydroxide solution (1.2 mL, 1.2 mmol), and [Rh(COD)Cl]₂ in dioxane (5.2 mL) was stirred at room temperature. After 5 hours, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then absorbed onto diatomaceous earth for purification by flash chromatography. MS(ESI): mass calcd. for C₂₄H₂₉N₃O₄, 423.2; m/z found, 424.2 [M+H]⁺.

Step B: Ethyl 3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. A mixture of ethyl 3-(3-(acetoxymethyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (279 mg, 0.659 mmol) and potassium carbonate (390 mg, 2.82 mmol) in ethanol (5 mL) was stirred at room temperature. After 24 hours, the mixture was partitioned between water and ethyl acetate. The layers were separated. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and then absorbed onto diatomaceous earth for purification by flash column chromatography (dichloromethane-methanol) to provide the title compound (178 mg, 71%) which was taken onto the next step without further characterization. MS(ESI): mass calcd. for C₂₂H₂₇N₃O₃, 381.2; m/z found, 382.2 [M+H]⁺. Alternatively, the title compound can also be prepared using analogous conditions as described in Step A above using (3-(hydroxymethyl)-4-methylphenyl)boronic acid instead of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate and triethyl amine instead of potassium hydroxide as base.

Step C: Ethyl 3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (176 mg) was prepared using analogous conditions as described in Example 7, Step A using (R)-6,7,7a,8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 83) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide and using ethyl 3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate instead of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS(ESI): mass calcd. for C₃₃H₃₉N₅O₄S, 601.3; m/z found, 602.3 [M+H]⁺.

Step D: 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (132 mg) was prepared using analogous conditions as described in Example 7, Step B using ethyl 3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate instead of ethyl 3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. MS (ESI): mass calcd. for C₃₁H₃₅N₅O₄S, 573.2; m/z found, 574.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.15 (t, J=7.4 Hz, 1H), 7.77-7.66 (m, 1H), 7.50-7.39 (m, 1H), 7.28-7.22 (m, 1H), 7.22-7.17 (m, 1H), 7.17-7.11 (m, 1H), 7.07-6.93 (m, 2H), 6.87-6.80 (m, 1H), 4.82-4.68 (m, 1H), 4.27-3.92 (m, 3H), 3.12-2.82 (m, 6H), 2.66-2.56 (m, 3H), 2.23 (s, 3H), 1.97-1.50 (m, 3H), 1.42-1.26 (m, 4H), 3.30-3.23 (m, 2H).

Example 279: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 278, 126 mg) were separated by chiral SFC (stationary phase: LUX-CEL-4, 2×25 cm; mobile phase: 40% methanol, 10% acetonitrile, 50% CO₂) to afford two diastereoisomers. The first eluting isomer (61 mg) was designated (*S): ¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.73-7.69 (m, 1H), 7.48-7.42 (m, 1H), 7.26-7.18 (m, 2H), 7.15-7.11 (m, 1H), 7.03-6.93 (m, 2H), 6.81-6.77 (m, 1H), 4.80-4.71 (m, 1H), 4.24-4.00 (m, 3H), 3.29-3.20 (m, 2H), 3.10-2.79 (m, 6H), 2.64 (s, 3H), 2.22 (s, 3H), 1.99-1.85 (m, 1H), 1.72-1.52 (m, 2H), 1.39-1.27 (m, 4H).

Example 280: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (63 mg) from the chiral separation described in Example 279 was designated (*R): ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (br s, 1H), 8.14 (d, J=7.0 Hz, 1H), 7.75-7.69 (m, 1H), 7.49-7.42 (m, 1H), 7.26-7.09 (m, 3H), 7.05-6.94 (m, 2H), 6.85 (d, J=7.2 Hz, 1H), 4.79-4.67 (m, 1H), 4.23-3.88 (m, 3H), 3.28-3.17 (m, 2H), 3.08-2.86 (m, 6H), 2.60 (s, 3H), 2.23 (s, 3H), 1.93-1.60 (m, 3H), 1.38-1.26 (m, 4H).

Example 281: 3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (50 mg) was prepared using analogous conditions as described in Example 278 using (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) instead of (R)-6,7,7a, 8,9,10-hexahydrobenzo[f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide in Step C. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.37-12.13 (s, 1H), 8.37-8.33 (m, 1H), 8.18-8.12 (m, 1H), 8.04-7.99 (m, 1H), 7.28-7.18 (m, 2H), 7.16-7.12 (m, 1H), 6.95-6.90 (m, 1H), 6.90-6.78 (m, 1H), 4.79-4.68 (m, 1H), 4.40-4.12 (m, 3H), 3.68-3.55 (m, 1H), 3.55-3.44 (m, 1H), 3.16-2.88 (m, 6H), 2.65-2.58 (m, 3H), 2.24-2.17 (m, 3H), 2.01-1.82 (m, 1H), 1.77-1.55 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.27 (m, 3H).

Example 282: (*S)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 281, 45 mg) were separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 50% methanol, 50% CO₂) to afford two diastereoisomers. The first eluting isomer (23 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36-8.32 (m, 1H), 8.13 (d, J=7.2 Hz, 1H), 8.03-7.97 (m, 1H), 7.25-7.17 (m, 2H), 7.12 (d, J=7.7 Hz, 1H), 6.92 (dd, J=7.8, 4.7 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 4.78-4.71 (m, 1H), 4.39-4.24 (m, 2H), 4.18-4.11 (m, 1H), 3.64-3.53 (m, 1H), 3.53-3.45 (m, 1H), 3.16-3.07 (m, 1H), 3.07-2.88 (m, 5H), 2.63 (s, 3H), 2.21 (s, 3H), 1.92 (d, J=19.0 Hz, 1H), 1.72-1.52 (m, 2H), 1.41 (d, J=11.5 Hz, 1H), 1.35-1.27 (m, 3H);

Example 283: (*R)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-ethyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (22 mg) from the chiral separation described in Example 282 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36-8.32 (m, 1H), 8.14 (d, J=7.3 Hz, 1H), 8.01 (dd, J=7.7, 1.8 Hz, 1H), 7.25-7.19 (m, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.95-6.90 (m, 1H), 6.84 (d, J=7.3 Hz, 1H), 4.78-4.68 (m, 1H), 4.31-4.14 (m, 3H), 3.67-3.56 (m, 1H), 3.51-3.43 (m, 1H), 3.12-2.86 (m, 6H), 2.59 (s, 3H), 2.21 (s, 3H), 1.92-1.81 (m, 1H), 1.69 (s, 2H), 1.40 (s, 1H), 1.35-1.26 (m, 3H).

Example 284: 3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (132 mg) was prepared using analogous conditions as described in Example 7 using 4,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 81) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₂₉H₂₉F₃N₄O₅S, 602.2; m/z found, 603.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.42 (d, J=7.1 Hz, 1H), 7.72-7.65 (m, 1H), 7.61-7.53 (m, 1H), 7.32-7.10 (m, 6H), 4.88-4.79 (m, 1H), 4.46-4.28 (m, 2H), 3.53-3.32 (m, 2H), 3.20-3.06 (m, 2H), 2.75 (s, 3H), 2.15 (s, 3H), 1.12-0.96 (m, 6H).

Example 285: (*S)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 284, 98 mg) were separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 45% ethanol, 55% CO₂) to afford two enantiomers. The first eluting isomer (39 mg) was designated (*S): MS (ESI): mass calcd. for C₂₉H₂₉F₃N₄O₅S, 602.2; m/z found, 603.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.41 (d, J=7.2 Hz, 1H), 7.69 (dd, J=7.7, 1.7 Hz, 1H), 7.60-7.53 (m, 1H), 7.32-7.27 (m, 1H), 7.26-7.20 (m, 2H), 7.20-7.10 (m, 3H), 4.88-4.81 (m, 1H), 4.44-4.29 (m, 2H), 3.55-3.33 (m, 2H), 3.17-3.06 (m, 2H), 2.74 (s, 3H), 2.15 (s, 3H), 1.12-0.99 (m, 6H).

Example 286: (*R)-3-(3-((4,4-Dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (43 mg) from the chiral separation described in Example 285 was designated (*R): MS (ESI): mass calcd. for C₂₉H₂₉F₃N₄O₅S, 602.2; m/z found, 603.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (s, 1H), 8.41 (d, J=7.2 Hz, 1H), 7.69 (dd, J=7.7, 1.7 Hz, 1H), 7.59-7.54 (m, 1H), 7.31-7.27 (m, 1H), 7.26-7.10 (m, 5H), 4.87-4.82 (m, 1H), 4.44-4.29 (m, 2H), 3.53-3.33 (m, 2H), 3.16-3.04 (m, 2H), 2.74 (s, 3H), 2.15 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H).

Example 287: 3-(3-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (96 mg) was prepared using analogous conditions as described in Example 7 using 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₂₉H₂₇F₃N₄O₆S, 616.2; m/z found, 617.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.36 (d, J=7.2 Hz, 1H), 7.78-7.73 (m, 1H), 7.72-7.66 (m, 1H), 7.48 (dd, J=8.1, 1.1 Hz, 1H), 7.43-7.36 (m, 1H), 7.31-7.25 (m, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.20-7.14 (m, 2H), 4.87-4.80 (m, 1H), 4.42 (d, J=7.5 Hz, 1H), 4.36 (d, J=7.6 Hz, 1H), 4.31 (d, J=7.5 Hz, 1H), 4.27-4.14 (m, 3H), 3.76-3.62 (m, 2H), 3.16-3.07 (m, 2H), 2.73 (s, 3H), 2.2 (s, 3H).

Example 288: (*R)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 287, 89 mg) were separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 45% ethanol, 55% CO₂) to afford two enantiomers. The first eluting isomer (43 mg) was Example 26 and designated (*S). The second eluting isomer was designated (*R): MS (ESI): mass calcd. for C₂₉H₂₇F₃N₄O₆S, 616.2; m/z found, 617.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.34 (s, 1H), 8.36 (d, J=7.1 Hz, 1H), 7.75 (dd, J=7.8, 1.7 Hz, 1H), 7.71-7.66 (m, 1H), 7.50-7.46 (m, 1H), 7.42-7.37 (m, 1H), 7.27 (dd, J=7.8, 2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.19-7.13 (m, 2H), 4.87-4.79 (m, 1H), 4.42 (d, J=7.5 Hz, 1H), 4.36 (d, J=7.6 Hz, 1H), 4.30 (d, J=7.6 Hz, 1H), 4.27-4.15 (m, 3H), 3.74-3.63 (m, 2H), 3.16-3.05 (m, 2H), 2.73 (s, 3H), 2.21 (s, 3H).

Example 289: 3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (171 mg) was prepared using analogous conditions as described in Example 7 using (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.44-8.39 (m, 1H), 8.33-8.29 (m, 1H), 8.00-7.95 (m, 1H), 7.33-7.27 (m, 1H), 7.24-7.14 (m, 3H), 6.94-6.89 (m, 1H), 4.89-4.77 (m, 1H), 4.36-4.14 (m, 3H), 4.09-4.01 (m, 1H), 3.29-3.02 (m, 5H), 2.78-2.70 (m, 3H), 2.20-2.12 (m, 3H), 1.62-1.09 (m, 6H).

Example 290: (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 289, 117 mg) were separated by chiral SFC (stationary phase: CHIRALPAK IA 2×25 cm; mobile phase: 40% methanol, 60% CO₂) to afford two diastereoisomers. The first eluting isomer (54 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H), 8.47-8.39 (m, 1H), 8.34-8.27 (m, 1H), 8.01-7.94 (m, 1H), 7.34-7.26 (m, 1H), 7.26-7.11 (m, 3H), 6.95-6.88 (m, 1H), 4.82 (t, J=7.7 Hz, 1H), 4.30-4.14 (m, 3H), 4.10-3.99 (m, 1H), 3.30-3.18 (m, 1H), 3.15-3.00 (m, 4H), 2.72 (s, 3H), 2.14 (s, 3H), 1.64-1.13 (m, 6H).

Example 291: (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (59 mg) from the chiral separation described in Example 290 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.2; m/z found, 629.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.41 (d, J=7.1 Hz, 1H), 8.33-8.28 (m, 1H), 8.00-7.95 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.19-7.13 (m, 2H), 6.94-6.89 (m, 1H), 4.91-4.77 (m, 1H), 4.38-4.21 (m, 2H), 4.19-4.01 (m, 2H), 3.25-2.99 (m, 5H), 2.76 (s, 3H), 2.17 (s, 3H), 1.58-1.04 (m, 6H).

Example 292: (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (93 mg) was prepared using analogous conditions as described in Example 7 using (*S)-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 113) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and the following chiral SFC conditions after Step B: stationary phase: Chiracel OD-H 5 μm 250×20 mm, mobile phase: 50% CO₂, 50% EtOH) to afford two diastereoisomers. The first eluting isomer was designated (*S): MS(ESI): mass calcd. for C₂₄H₂₇F₃N₆O₄S, 600.2; m/z found, 601.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.58-12.14 (s, 1H), 8.42-8.37 (m, 2H), 8.02-7.98 (dd, J=7.7, 1.7 Hz, 1H), 7.34-7.30 (d, J=2.1 Hz, 1H), 7.27-7.23 (m, 1H), 7.21-7.17 (d, J=7.3 Hz, 1H), 7.17-7.13 (d, J=7.9 Hz, 1H), 7.02-6.98 (dd, J=7.7, 4.9 Hz, 1H), 4.86-4.78 (m, 1H), 4.55-4.46 (m, 1H), 4.46-4.39 (d, J=14.4 Hz, 1H), 4.17-4.09 (m, 1H), 4.09-4.01 (d, J=14.4 Hz, 1H), 3.68-3.61 (m, 1H), 3.60-3.53 (m, 1H), 3.14-3.08 (d, J=7.8 Hz, 2H), 2.95-2.88 (m, 1H), 2.76-2.71 (s, 3H), 2.28-2.23 (s, 3H), 2.21-2.11 (m, 1H), 2.10-2.02 (m, 1H).

Example 293: (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (94 mg) from the chiral separation described in Example 292 was designated (*R): MS(ESI): mass calcd. for C₂₄H₂₇F₃N₆O₄S, 600.2; m/z found, 601.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.49-12.17 (s, 1H), 8.41-8.37 (m, 2H), 8.02-7.98 (m, 1H), 7.33-7.29 (d, J=2.0 Hz, 1H), 7.26-7.22 (m, 1H), 7.18-7.13 (m, 2H), 7.02-6.98 (dd, J=7.7, 4.8 Hz, 1H), 4.85-4.77 (m, 1H), 4.50-4.39 (m, 2H), 4.15-4.06 (m, 1H), 4.06-4.01 (d, J=14.2 Hz, 1H), 3.66-3.52 (m, 2H), 3.17-3.02 (m, 2H), 2.91-2.84 (m, 1H), 2.76-2.71 (s, 3H), 2.28-2.23 (s, 3H), 2.18-2.08 (m, 1H), 1.98-1.90 (m, 1H).

Example 294: (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (101 mg) was prepared using analogous conditions as described in Example 26 using (*R)-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 114) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and the chiral SFC conditions as described in Example 292 to afford two diastereoisomers after Step B. The first eluting isomer was designated (*S): MS(ESI): mass calcd. for C₂₄H₂₇F₃N₆O₄S, 600.2; m/z found, 601.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.31 (s, 1H), 8.41-8.37 (m, 2H), 8.02-7.98 (m, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.26-7.21 (m, 1H), 7.17-7.14 (m, 2H), 7.00 (dd, J=7.7, 4.8 Hz, 1H), 4.85-4.78 (m, 1H), 4.50-4.40 (m, 2H), 4.15-4.06 (m, 1H), 4.04 (d, J=14.2 Hz, 1H), 3.66-3.53 (m, 2H), 3.17-3.03 (m, 2H), 2.91-2.83 (m, 1H), 2.74 (s, 3H), 2.26 (s, 3H), 2.18-2.08 (m, 1H), 1.98-1.90 (m, 1H).

Example 295: (*R)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9-tetrahydro-6H-azeto[2,1-d]pyrido[2,3-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (103 mg) from the chiral separation described in Example 294 was designated (*R): MS(ESI): mass calcd. for C₂₄H₂₇F₃N₆O₄S, 600.2; m/z found, 601.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.42-8.37 (m, 2H), 8.01-7.98 (m, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.27-7.23 (m, 1H), 7.19 (d, J=7.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.02-6.97 (m, 1H), 4.85-4.78 (m, 1H), 4.53-4.45 (m, 1H), 4.42 (d, J=14.3 Hz, 1H), 4.16-4.09 (m, 1H), 4.05 (d, J=14.4 Hz, 1H), 3.69-3.61 (m, 1H), 3.61-3.52 (m, 1H), 3.10 (d, J=7.8 Hz, 2H), 2.95-2.88 (m, 1H), 2.74 (s, 3H), 2.25 (s, 3H), 2.21-2.10 (m, 1H), 2.08-2.02 (m, 1H).

Example 296: 3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (92 mg) was prepared using analogous conditions as described in Example 7 using (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4) instead of 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide, ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-ethylpyridin-2-yl)propanoate (Intermediate 115) instead of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, and di-tert-butyl azodicarboxylate instead of diisopropyl azodicarboxylate in Step A. MS(ESI): mass calcd. for C₂₉H₃₃N₇O₄S, 575.2; m/z found, 576.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.18-11.99 (s, 1H), 8.35-8.32 (m, 1H), 8.03-7.99 (m, 1H), 7.59-7.54 (d, J=8.7 Hz, 1H), 7.51-7.46 (m, 1H), 7.45-7.40 (m, 1H), 7.22-7.14 (dd, J=17.9, 7.8 Hz, 1H), 6.93-6.87 (m, 1H), 4.99-4.89 (m, 1H), 4.72-4.59 (m, 2H), 4.54-4.39 (m, 2H), 4.36-4.23 (m, 1H), 3.69-3.47 (m, 2H), 3.46-3.35 (m, 1H), 3.33-3.20 (m, 2H), 2.99-2.87 (m, 1H), 2.87-2.80 (m, 3H), 2.27-2.17 (m, 3H), 2.10-1.94 (m, 1H), 1.93-1.84 (m, 1H), 1.84-1.73 (m, 1H), 1.57-1.38 (m, 4H).

Example 297: (*S)-3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of 3-(6-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 296, 68 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 2×25 cm; mobile phase: 35% ethanol, 65% CO₂) to afford two diastereoisomers. The first eluting isomer (28 mg) was designated (*S): MS(ESI): mass calcd. for C₂₉H₃₃N₇O₄S, 575.2; m/z found, 576.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.41-11.82 (m, 1H), 8.35-8.31 (m, 1H), 8.03-7.98 (m, 1H), 7.58-7.54 (m, 1H), 7.51-7.47 (m, 1H), 7.44-7.39 (m, 1H), 7.22-7.17 (m, 1H), 6.92-6.87 (m, 1H), 4.97-4.90 (m, 1H), 4.69-4.61 (m, 2H), 4.51-4.40 (m, 2H), 4.30-4.23 (m, 1H), 3.64-3.47 (m, 2H), 3.29-3.20 (m, 3H), 2.97-2.88 (m, 1H), 2.86-2.79 (m, 3H), 2.25-2.20 (m, 3H), 2.06-1.93 (m, 1H), 1.84-1.71 (m, 2H), 1.49-1.36 (m, 4H).

Example 298: (*R)-3-(6-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (31 mg) from the chiral separation described in Example 297 was designated (*R): MS(ESI): mass calcd. for C₂₉H₃₃N₇O₄S, 575.2; m/z found, 576.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36-8.31 (dd, J=4.8, 1.8 Hz, 1H), 8.04-7.99 (dd, J=7.8, 1.8 Hz, 1H), 7.57-7.53 (m, 1H), 7.49-7.41 (m, 2H), 7.18-7.13 (d, J=7.8 Hz, 1H), 6.93-6.88 (m, 1H), 4.98-4.91 (m, 1H), 4.70-4.60 (m, 2H), 4.50-4.38 (m, 2H), 4.36-4.27 (m, 1H), 3.67-3.57 (m, 1H), 3.57-3.47 (m, 1H), 3.44-3.32 (m, 3H), 2.93-2.80 (m, 4H), 2.25-2.17 (s, 3H), 2.10-1.94 (m, 1H), 1.92-1.82 (m, 2H), 1.57-1.41 (m, 4H).

Example 299: (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (113 mg) was prepared using analogous conditions as described in Example 26 using (*S)-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 76) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS(ESI): mass calcd. for C₃₁H₃₂F₃N₅O₄S, 627.2; m/z found, 628.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.51-12.16 (s, 1H), 8.42-8.37 (d, J=7.1 Hz, 1H), 7.71-7.66 (m, 1H), 7.52-7.45 (m, 1H), 7.33-7.27 (m, 1H), 7.27-7.08 (m, 5H), 4.85-4.77 (m, 1H), 4.42-4.31 (d, J=14.0 Hz, 1H), 4.05-3.95 (m, 1H), 3.71-3.58 (m, 1H), 3.48-3.38 (m, 1H), 3.27-3.02 (m, 4H), 2.77-2.71 (s, 3H), 2.65-2.52 (m, 1H), 2.27-2.20 (s, 3H), 1.72-1.36 (m, 3H), 1.36-0.97 (m, 3H).

Example 300: (*S)-3-(3-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (107 mg) was prepared using analogous conditions as described in Example 26 using (*R)-7,7a,8,9,10,11-hexahydro-6H-benzo[f]pyrido[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 116) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS(ESI): mass calcd. for C₃₁H₃₂F₃N₅O₄S, 627.2; m/z found, 628.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.36-12.27 (s, 1H), 8.43-8.37 (d, J=7.1 Hz, 1H), 7.70-7.64 (dd, J=7.9, 1.6 Hz, 1H), 7.50-7.44 (m, 1H), 7.32-7.27 (m, 1H), 7.26-7.14 (m, 4H), 7.12-7.05 (m, 1H), 4.87-4.76 (m, 1H), 4.34-4.24 (d, J=14.1 Hz, 1H), 4.17-4.03 (d, J=14.1 Hz, 1H), 3.84-3.67 (s, 1H), 3.41-3.24 (m, 1H), 3.24-3.05 (m, 3H), 2.76-2.71 (s, 4H), 2.27-2.20 (s, 3H), 1.66-1.42 (m, 1H), 1.34-1.10 (m, 6H).

Example 301: 3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (108 mg) was prepared using analogous conditions as described in Example 296 using (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) instead of (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₅N₇O₄S, 589.2; m/z found, 590.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35-8.29 (m, 1H), 8.09-8.03 (m, 1H), 7.45-7.37 (dd, J=12.1, 7.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.24-7.17 (m, 1H), 6.95-6.81 (m, 2H), 5.11-4.99 (m, 1H), 4.79-4.53 (m, 4H), 4.44-4.27 (m, 2H), 3.71-3.29 (m, 4H), 3.11-2.93 (m, 1H), 2.93-2.88 (m, 3H), 2.39-2.31 (m, 3H), 1.87-1.48 (m, 9H).

Example 302: (*S)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of 3-(6-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 301, 99 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 3×25 cm; mobile phase: 45% methanol, 55% CO₂) to afford two diastereoisomers. The first eluting isomer (44 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₅N₇O₄S, 589.2; m/z found, 590.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.33-8.29 (m, 1H), 8.00-7.96 (m, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 6.93-6.90 (m, 1H), 5.02-4.92 (m, 1H), 4.70-4.62 (m, 2H), 4.53 (d, J=14.2 Hz, 1H), 4.47-4.39 (m, 1H), 4.29 (d, J=14.2 Hz, 1H), 4.24-4.15 (m, 1H), 3.73-3.63 (m, 1H), 3.44-3.25 (m, 3H, coincident with water), 2.93 (dd, J=16.3, 7.1 Hz, 1H), 2.85 (s, 3H), 2.17 (s, 3H), 1.76-1.55 (m, 3H), 1.51-1.41 (m, 6H).

Example 303: (*R)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (44 mg) from the chiral separation described in Example 302 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₅N₇O₄S, 589.2; m/z found, 590.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H), 8.32-8.29 (m, 1H), 8.00-7.95 (m, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 6.93-6.89 (m, 1H), 5.01-4.91 (m, 1H), 4.70-4.61 (m, 2H), 4.53 (d, J=13.7 Hz, 1H), 4.43-4.35 (m, 1H), 4.25-4.15 (m, 2H), 3.56-3.47 (m, 1H), 3.38-3.21 (m, 2H), 3.17-3.11 (m, 1H), 3.03-2.94 (m, 1H), 2.84 (s, 3H), 2.19 (s, 3H), 1.68-1.51 (m, 3H), 1.48-1.41 (m, 3H), 1.34-1.16 (m, 3H).

Example 304: 3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The title compound (96 mg) was prepared using analogous conditions as described in Example 301 using (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3) instead of (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₅N₇O₄S, 589.2; m/z found, 590.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35-8.29 (m, 1H), 8.08-8.04 (m, 1H), 7.45-7.37 (m, 1H), 7.32-7.24 (m, 1H), 7.24-7.17 (m, 1H), 6.95-6.81 (m, 2H), 5.10-4.99 (m, 1H), 4.76-4.53 (m, 4H), 4.42-4.27 (m, 2H), 3.72-3.29 (m, 4H), 3.10-2.95 (m, 1H), 2.93-2.87 (m, 3H), 2.40-2.31 (m, 3H), 1.87-1.45 (m, 9H).

Example 305: (*S)-3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The mixture of 3-(6-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid isomers (Example 304, 89 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 3×25 cm; mobile phase: 45% ethanol, 55% CO₂) to afford two diastereoisomers. The first eluting isomer (40 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₅N₇O₄S, 589.2; m/z found, 590.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (s, 1H), 8.32-8.29 (m, 1H), 7.98 (dd, J=7.8, 1.8 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.53-7.50 (m, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 6.93-6.89 (m, 1H), 4.96 (t, J=7.7 Hz, 1H), 4.68-4.61 (m, 2H), 4.53 (d, J=13.7 Hz, 1H), 4.44-4.36 (m, 1H), 4.25-4.14 (m, 2H), 3.55-3.46 (m, 1H), 3.29-3.20 (m, 2H), 3.18-3.11 (m, 1H), 3.04-2.95 (m, 1H), 2.84 (s, 3H), 2.19 (s, 3H), 1.68-1.50 (m, 3H), 1.47-1.42 (m, 3H), 1.33-1.16 (m, 3H).

Example 306: (*R)-3-(6-(((*R)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid

The second eluting isomer (42 mg) from the chiral separation described in Example 305 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₅N₇O₄S, 589.2; m/z found, 590.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.34-8.29 (m, 1H), 7.99 (dd, J=7.8, 1.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.92 (dd, J=7.8, 4.6 Hz, 1H), 5.01-4.95 (m, 1H), 4.69-4.63 (m, 2H), 4.53 (d, J=14.3 Hz, 1H), 4.47-4.40 (m, 1H), 4.29 (d, J=14.3 Hz, 1H), 4.23-4.17 (m, 1H), 3.73-3.63 (m, 1H), 3.44-3.34 (m, 3H), 2.97-2.90 (m, 1H), 2.85 (s, 3H), 2.17 (s, 3H), 1.76-1.56 (m, 3H), 1.52-1.39 (m, 6H).

Example 307: (*S)-3-(4-methyl-34(*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (82 mg) was prepared using analogous conditions as described in Example 26 using (*S)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 77) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₄S, 642.2; m/z found, 643.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.17-8.11 (m, 1H), 8.03-7.98 (d, J=7.2 Hz, 1H), 7.89-7.85 (m, 1H), 7.21-7.17 (d, J=2.0 Hz, 1H), 7.16-7.11 (m, 1H), 7.08-7.03 (m, 1H), 6.91-6.88 (d, J=7.2 Hz, 1H), 4.97-4.90 (m, 1H), 4.51-4.37 (m, 2H), 4.30-4.22 (m, 1H), 4.22-4.11 (m, 1H), 3.31-3.23 (m, 2H), 3.23-3.12 (m, 2H), 3.10-2.99 (m, 1H), 2.87-2.78 (s, 3H), 2.28-2.26 (s, 3H), 2.26-2.24 (s, 3H), 1.79-0.78 (m, 6H).

Example 308: (*S)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (142 mg) was prepared using analogous conditions as described in Example 26 using (*R)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 117) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A and ethanol as a co-solvent in Step B. MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₄S, 642.2; m/z found, 643.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.16-8.10 (m, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.90-7.84 (m, 1H), 7.19-7.11 (m, 2H), 7.10-7.04 (m, 1H), 6.87 (d, J=7.3 Hz, 1H), 4.99-4.92 (m, 1H), 4.48-4.39 (m, 2H), 4.21 (d, J=14.7 Hz, 1H), 4.18-4.10 (m, 1H), 3.23-3.11 (m, 4H), 3.08-2.98 (m, 1H), 2.85 (s, 3H), 2.27 (s, 6H), 1.71-1.23 (m, 6H).

Example 309: (*S)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (181 mg) was prepared using analogous conditions as described in Example 26 using (*S)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 78) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₀F₄N₆O₄S, 646.2; m/z found, 647.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J=2.9 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.82-7.78 (m, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.16-7.12 (m, 1H), 7.09-7.05 (m, 1H), 6.91 (d, J=7.3 Hz, 1H), 4.98-4.90 (m, 1H), 4.52-4.38 (m, 2H), 4.25 (d, J=15.1 Hz, 1H), 4.21-4.11 (m, 1H), 3.32-3.24 (m, 2H), 3.24-3.13 (m, 2H), 3.10-3.01 (m, 1H), 2.82 (s, 3H), 2.25 (s, 3H), 1.82-1.36 (m, 6H).

Example 310: (*S)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (250 mg) was prepared using analogous conditions as described in Example 26 using (*R)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 79) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₀F₄N₆O₄S, 646.2; m/z found, 647.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J=3.0 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.83-7.78 (m, 1H), 7.18-7.13 (m, 2H), 7.12-7.07 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 4.98-4.92 (m, 1H), 4.50-4.38 (m, 2H), 4.21 (d, J=14.7 Hz, 1H), 4.18-4.10 (m, 1H), 3.27-3.13 (m, 4H), 3.09-3.01 (m, 1H), 2.84 (s, 3H), 2.27 (s, 3H), 1.76-1.25 (m, 6H).

Example 311: (*S)-3-(3-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (68 mg) was prepared using analogous conditions as described in Example 26 using 8′-fluoro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 80) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₂₄H₂₅F₄N₅O₅S, 619.2; m/z found, 620.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=3.0 Hz, 1H), 8.03-7.98 (m, 2H), 7.17-7.10 (m, 2H), 7.07-7.02 (m, 1H), 6.86 (d, J=7.2 Hz, 1H), 4.97-4.89 (m, 1H), 4.40-4.28 (m, 2H), 3.55 (s, 2H), 3.21-3.11 (m, 1H), 3.06-2.97 (m, 1H), 2.81 (s, 3H), 2.28 (s, 3H), 1.23-1.10 (m, 2H), 0.62-0.48 (m, 2H).

Example 312: (*S)-3-(3-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (934 mg) was prepared using analogous conditions as described in Example 26 using 7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 9) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₃₁H₃₀F₃N₇O₄S, 653.2; m/z found, 654.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.47-8.39 (m, 2H), 7.34-7.13 (m, 4H), 4.88-4.76 (m, 1H), 4.53-4.07 (m, 4H), 3.38-3.08 (m, 5H), 2.79-2.71 (m, 3H), 2.16-2.10 (m, 3H), 1.69-1.12 (m, 6H).

Example 313: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Methyl 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Di-tert-butyl azodicarboxylate (204 mg, 0.865 mmol) was added to a mixture of 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluormethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 48, 222 mg, 0.51 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 162 mg, 0.672 mmol), and triphenylphosphine (204 mg, 0.768 mmol) in THF (6.7 mL). After stirring overnight, the mixture was directly loaded onto silica gel for purification by flash column chromatography (ethyl acetatehexanes) to afford the title compound (352 mg) which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₅S, 657.2; m/z found, 658.2 [M+H]⁺.

Step B: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Methyl 2,2-dimethyl-3-[4-methyl-3-[(8-methyl-1,1-dioxo-spiro[3H-pyrido[2,3-b][1,4,5]oxathiazepine-4,1′-cyclopropane]-2-yl)methyl]phenyl]-3-((8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]propanoate (352 mg, 0.535 mmol) was dissolved in pyridine (15 mL) and the mixture was flushed with argon. Lithium iodide (291 mg, 2.17 mmol) was added and the mixture was heated in a microwave reactor at 150° C. for 2 hours. The mixture was concentrated and purified by basic reverse phase HPLC (C18, acetonitrile-water, 20 nM NH₄OH). MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.2; m/z found, 644.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 8.38 (d, J=7.1 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.27 (d, J=7.3 Hz, 1H), 7.23-7.15 (m, 1H), 7.15-7.05 (m, 2H), 4.76 (s, 1H), 4.25-4.10 (m, 2H), 3.61-3.17 (m, 2H), 2.61 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H), 1.32-1.14 (m, 6H), 0.97-0.81 (m, 2H), 0.64-0.44 (m, 2H).

Example 314: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 313, 215 mg) were separated by chiral SFC (stationary phase: Chiralpak IG 5 μm 2×25 cm; mobile phase: 30% ethanol-DCM (4:1), 70% CO₂) to afford two enantiomers. The first eluting isomer (67 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.2; m/z found, 644.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.39 (d, J=7.3 Hz, 1H), 8.33 (dd, J=2.2, 0.9 Hz, 1H), 8.08 (dd, J=2.2, 0.9 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.23-7.17 (m, 1H), 7.17-7.07 (m, 2H), 4.77 (s, 1H), 4.26-4.11 (m, 2H), 3.65-3.36 (m, 2H), 2.62 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 0.97-0.81 (m, 2H), 0.63-0.45 (m, 2H).

Example 315: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (70 mg) from the chiral separation described in Example 314 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.2; m/z found, 644.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 8.39 (d, J=7.3 Hz, 1H), 8.34-8.29 (m, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.21-7.16 (m, 1H), 7.16-7.07 (m, 2H), 4.77 (s, 1H), 4.25-4.09 (m, 2H), 3.59-3.39 (m, 2H), 2.62 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H), 1.27 (s, 3H), 1.21 (s, 3H), 0.96-0.83 (m, 2H), 0.62-0.44 (m, 2H).

Example 316: 3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (157 mg) was prepared using analogous conditions as described in Example 61 using 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 5) instead of 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54-8.50 (m, 1H), 8.39 (d, J=7.3 Hz, 1H), 8.26 (dd, J=7.6, 1.9 Hz, 1H), 7.53-7.48 (m, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.21-7.15 (m, 1H), 7.14-7.08 (m, 2H), 4.76 (s, 1H), 4.26-4.11 (m, 2H), 3.62-3.39 (m, 2H), 2.61 (s, 3H), 2.24 (s, 3H), 1.26 (s, 3H), 1.19 (s, 3H), 0.98-0.84 (m, 2H), 0.66-0.49 (m, 2H).

Example 317: (*S)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 316, 150 mg) were separated by chiral SFC (stationary phase: Chiralpak IG 5 μm 2×25 cm; mobile phase: 30% ethanol-DCM (4:1), 70% CO₂) to afford two enantiomers. The first eluting isomer (22 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.54-8.50 (m, 1H), 8.40 (d, J=7.2 Hz, 1H), 8.26 (dd, J=7.6, 1.9 Hz, 1H), 7.54-7.48 (m, 1H), 7.26 (d, J=7.3 Hz, 1H), 7.22-7.17 (m, 1H), 7.15-7.09 (m, 2H), 4.77 (s, 1H), 4.28-4.14 (m, 2H), 3.61-3.38 (m, 2H), 2.62 (s, 3H), 2.24 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 0.98-0.84 (m, 2H), 0.66-0.50 (m, 2H).

Example 318: (*R)-3-(3-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (22 mg) from the chiral separation described in Example 317 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54-8.48 (m, 1H), 8.39 (d, J=7.2 Hz, 1H), 8.26 (dd, J=7.6, 1.9 Hz, 1H), 7.53-7.47 (m, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.21-7.15 (m, 1H), 7.15-7.06 (m, 2H), 4.76 (s, 1H), 4.26-4.12 (m, 2H), 3.63-3.39 (m, 2H), 2.61 (s, 3H), 2.24 (s, 3H), 1.26 (s, 3H), 1.19 (s, 3H), 0.97-0.81 (m, 2H), 0.67-0.49 (m, 2H).

Example 319: 3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A 25% solution of sodium methoxide in methanol (1 mL) was added to a solution of methyl 2,2-dimethyl-3-(4-methyl-3-((pivaloyloxy)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 122, 438 mg, 0.866 mmol) in methanol (2 mL). After 2 hours, the mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated, and the organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound as an amber oil. MS (ESI): mass calcd. for C₂₁H₂₂F₃N₃O₃, 421.2; m/z found, 422.1 [M+H]⁺.

Step B: 3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (150 mg) was prepared using analogous conditions as described in Example 26 using methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate instead of (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36) was used instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.55 (s, 1H), 8.54 (dd, J=4.9, 1.9 Hz, 1H), 8.48 (d, J=7.2 Hz, 1H), 8.17 (dd, J=7.6, 1.9 Hz, 1H), 7.98-7.94 (m, 1H), 7.45-7.41 (m, 1H), 7.30 (d, J=1.9 Hz, 1H), 7.27-7.22 (m, 1H), 7.19-7.14 (m, 1H), 7.04-7.00 (m, 1H), 4.59 (s, 1H), 4.45 (s, 2H), 3.82-3.71 (m, 2H), 3.63-3.33 (m, 4H), 2.20 (s, 3H), 1.56-1.42 (m, 4H), 1.30-1.22 (m, 6H).

Example 320: (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 319, 146 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 2×25 cm; mobile phase: 45% ethanol, 55% CO₂) to afford two enantiomers. The first eluting isomer (63 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 8.56-8.51 (m, 1H), 8.48 (d, J=7.1 Hz, 1H), 8.19-8.13 (m, 1H), 7.96 (s, 1H), 7.45-7.40 (m, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.27-7.22 (m, 1H), 7.17-7.13 (m, 1H), 7.02 (dd, J=7.2, 1.7 Hz, 1H), 4.59 (s, 1H), 4.48-4.41 (m, 2H), 3.84-3.69 (m, 2H), 3.64-3.38 (m, 4H), 2.20 (s, 3H), 1.55-1.42 (m, 4H), 1.27 (s, 3H), 1.25 (s, 3H).

Example 321: (*R)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (61 mg) from the chiral separation described in Example 320 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 8.53 (dd, J=4.8, 2.0 Hz, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.17 (dd, J=7.6, 1.9 Hz, 1H), 7.96 (s, 1H), 7.46-7.39 (m, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.27-7.22 (m, 1H), 7.17-7.13 (m, 1H), 7.02 (dd, J=7.2, 1.7 Hz, 1H), 4.59 (s, 1H), 4.48-4.42 (m, 2H), 3.84-3.70 (m, 2H), 3.66-3.33 (m, 4H), 2.20 (s, 3H), 1.55-1.41 (m, 4H), 1.26 (s, 3H), 1.24 (s, 3H).

Example 322: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (186 mg) was prepared using analogous conditions as described in Example 26 using methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 319, Step A) instead of (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6) instead of 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide in Step A. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H), 8.46 (d, J=7.1 Hz, 1H), 8.35-8.30 (m, 1H), 8.08 (dd, J=2.2, 0.9 Hz, 1H), 7.95 (s, 1H), 7.26-7.13 (m, 3H), 7.03-6.97 (m, 1H), 4.55 (s, 1H), 4.28-4.17 (m, 2H), 3.66-3.39 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 1.28-1.17 (m, 6H), 0.99-0.87 (m, 2H), 0.69-0.54 (m, 2H).

Example 323: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 322, 75 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 2×25 cm; mobile phase: 40% ethanol, 60% CO₂) to afford two enantiomers. The first eluting isomer (35 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H), 8.46 (d, J=7.1 Hz, 1H), 8.35-8.30 (m, 1H), 8.08 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 7.25-7.14 (m, 3H), 7.01-6.97 (m, 1H), 4.55 (s, 1H), 4.29-4.16 (m, 2H), 3.64-3.51 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 1.27-1.20 (m, 6H), 0.99-0.86 (m, 2H), 0.68-0.54 (m, 2H).

Example 324: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (31 mg) from the chiral separation described in Example 323 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (d, J=7.1 Hz, 1H), 8.34-8.29 (m, 1H), 8.11-8.06 (m, 1H), 7.95 (s, 1H), 7.23-7.11 (m, 3H), 6.99 (dd, J=7.3, 1.7 Hz, 1H), 4.54 (s, 1H), 4.27-4.13 (m, 2H), 3.66-3.38 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 1.21-1.14 (m, 6H), 0.98-0.84 (m, 2H), 0.69-0.53 (m, 2H).

Example 325: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: 2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The title compound (90 mg) was prepared using analogous conditions as described in Example 38 using 7′-((2-morpholinoethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 146) instead of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step D.

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-64(7′-(2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The mixture of 2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers (85 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 2×25 cm; mobile phase: 20% ethanol with 0.1% ammonium hydroxide, 80% CO₂) to afford two enantiomers. The first eluting isomer (39 mg) was designated (*S): MS (ESI): mass calcd. for C₃₇H₄₄F₃N₇O₈S, 803.3; m/z found, 804.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=8.5 Hz, 1H), 7.96 (d, J=7.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.29-7.26 (m, 1H coincident with chloroform), 7.07 (d, J=7.9 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 4.79 (s, 1H), 4.72-4.66 (m, 1H), 4.57-4.47 (m, 3H), 4.12-4.03 (m, 2H), 3.85-3.72 (m, 8H), 2.94 (s, 3H), 2.80 (t, J=5.8 Hz, 2H), 2.61-2.55 (m, 4H), 2.37 (s, 3H), 1.86-1.72 (m, 4H coincident with water), 1.42 (s, 3H), 1.41 (s, 3H).

Example 326: (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-64(7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (40 mg) from the chiral separation described in Example 325 was designated (*R): MS (ESI): mass calcd. for C₃₇H₄₄F₃N₇O₈S, 803.3; m/z found, 804.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=8.5 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.25-7.23 (m, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 4.79 (s, 1H), 4.72-4.66 (m, 1H), 4.57-4.47 (m, 3H), 4.12-4.03 (m, 2H), 3.86-3.72 (m, 8H), 2.94 (s, 3H), 2.80 (t, J=5.8 Hz, 2H), 2.60-2.56 (m, 4H), 2.37 (s, 3H), 1.88-1.73 (m, 4H), 1.43 (s, 3H), 1.41 (s, 3H).

Example 327: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-64(7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: (6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. A 1.6 M solution of n-butyllithium in hexanes (6 mL, 9.6 mmol) was added dropwise to a solution of 6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpyridine (Intermediate 120, 3 g, 9.5 mmol) in THF (20 mL) which had been cooled to 78° C. After 30 seconds, a solution of 1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (1.5 g, 6.7 mmol) in THF (14 mL) was added. After 2 minutes, saturated aqueous ammonium chloride solution (5 mL) was added and the flask was removed from the cooling bath. After reaching room temperature, the mixture was partitioned between ethyl acetate and water and the layers were separated. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (RediSep Gold C18 column, eluting with water-acetonitrile with 0.05% v/v TFA) to afford the title compound (608 mg, 20%). MS (ESI): mass calcd. for C₂₅H₃₆N₄O₂Si, 452.3; m/z found, 453.3 [M+H]⁺.

Step B: tert-Butyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. DBU (0.05 mL, 0.3 mmol) was added to a mixture of trichloroacetonitrile (0.3 mL, 3 mmol) and (6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (608 mg, 1.34 mmol) in acetonitrile (10 mL). After 1 hour, ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (Intermediate 20, 1.5 g, 6.6 mmol) and then a solution of trifluoromethansulfonimide (275 mg, 1 mmol) in acetonitrile (1 mL) were added in sequence. After 1 hour, saturated aqueous sodium bicarbonate solution was added and the mixture was partitioned between brine and ethyl acetate. The layers were separated. The organic extracts were dried over anhydrous sodium sulfate, filtered, and absorbed onto diatomaceous earth for purification by flash column chromatography (hexanes-ethyl acetate) to afford the title compound (368 mg, 47%). MS (ESI): mass calcd. for C₃₃H₅₀N₄O₃Si, 578.4; m/z found, 579.3 [M+H]⁺.

Step C: tert-Butyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. A 1 M solution of TBAF in THF (1 mL, 1 mmol) was added to a solution of tert-butyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (368 mg, 0.636 mmol) in THF (4 ml). After 2 hours, the mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated. The organic extracts were dried over anhydrous sodium sulfate, filtered, and absorbed onto diatomaceous earth purification by flash column chromatography (hexanes-ethyl acetate) to afford the title compound (266 mg, 90%). MS (ESI): mass calcd. for C₂₇H₃₆N₄O₃, 464.3; m/z found, 465.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=8.7 Hz, 1H), 7.43-7.35 (m, 1H), 7.28 (d, J=8.8 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 5.07 (s, 1H), 4.71-4.64 (m, 1H), 4.64-4.59 (m, 1H), 4.59-4.56 (m, 1H), 4.56-4.50 (m, 2H), 2.85 (s, 3H), 2.19 (s, 3H), 1.39-1.28 (m, 3H), 1.20 (s, 9H), 1.10 (s, 3H), 0.57-0.40 (m, 4H).

Step D: tert-Butyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. The title compound (372 mg) was prepared using analogous conditions as described in Example 38, Step D using tert-Butyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate instead of methyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and 7′-(2-morpholinoethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 146) instead of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₄₄H₅₉N₇O₈S, 845.4; m/z found, 846.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.34-7.29 (m, 2H), 6.91 (d, J=7.9 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 5.07 (s, 1H), 4.79 (d, J=13.8 Hz, 1H), 4.53-4.38 (m, 5H), 4.10-4.02 (m, 2H), 3.81-3.59 (m, 8H), 1.52-1.44 (m, 3H), 2.95 (s, 3H), 2.83-2.74 (m, 2H), 2.63-2.53 (m, 4H), 2.36 (s, 3H), 1.95-1.85 (m, 1H), 1.77-1.57 (m, 4H), 1.42-1.32 (m, 1H), 1.21 (s, 11H), 0.66-0.59 (m, 2H), 0.50-0.43 (m, 2H).

Step E: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-64(7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. TFA (1 mL) was added to a solution of tert-butyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′z,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (344 mg, 0.407 mmol) in DCM (4 mL). The solution was heated at 50° C. After 3 hours, additional TFA (1 mL) was added and the mixture was stirred overnight. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved in water and the pH was adjusted to 4-5 by addition of 1 M aqueous HCl solution. The aqueous portion was extracted with ethyl acetate which resulted in multiple organic extracts which were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (XBridge OBD C18 column, 50×250 mm, eluent: 20 mM aqueous ammonia-acetonitrile) to afford the title compound (221 mg, 69%). MS (ESI): mass calcd. for C₄₀H₅₁N₇O₈S, 789.6; m/z found, 790.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.5 Hz, 1H), 7.53-7.45 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 4.78 (s, 1H), 4.69-4.62 (m, 2H), 4.50 (s, 1H), 4.41 (d, J=7.0 Hz, 2H), 4.18-3.62 (m, 12H), 3.01 (s, 3H), 2.89-2.49 (m, 5H), 2.38 (s, 3H), 1.84-1.69 (m, 4H), 1.44 (s, 3H), 1.36-1.20 (m, 4H), 0.65-0.55 (m, 2H), 0.48-0.41 (m, 2H).

Example 328: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers (Example 327, 197 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H 2×25 cm; mobile phase: 40% ethanol with 0.1% ammonia-methanol, 60% CO₂) to afford two enantiomers. The first eluting isomer (94 mg) was designated (*S): MS (ESI): mass calcd. for C₄₀H₅₁N₇O₈S, 789.6; m/z found, 790.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.5 Hz, 1H), 7.53-7.47 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.78 (s, 1H), 4.69-4.61 (m, 2H), 4.49 (t, J=5.8 Hz, 2H), 4.41 (d, J=7.1 Hz, 2H), 4.15-4.03 (m, 2H), 3.88-3.81 (m, 1H), 3.81-3.68 (m, 7H), 3.01 (s, 3H), 2.80 (t, J=5.8 Hz, 2H), 2.61-2.55 (m, 4H), 2.38 (s, 3H), 1.85-1.69 (m, 4H), 1.44 (s, 3H), 1.36-1.31 (m, 4H), 0.65-0.57 (m, 2H), 0.49-0.40 (m, 2H).

Example 329: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (97 mg) from the chiral separation described in Example 328 was designated (*R): MS (ESI): mass calcd. for C₄₀H₅₁N₇O₈S, 789.6; m/z found, 790.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.78 (s, 1H), 4.71-4.61 (m, 2H), 4.52-4.46 (m, 2H), 4.41 (d, J=7.1 Hz, 2H), 4.14-4.03 (m, 2H), 3.88-3.81 (m, 1H), 3.81-3.70 (m, 7H), 3.01 (s, 3H), 2.80 (t, J=5.8 Hz, 2H), 2.61-2.55 (m, 4H), 2.38 (s, 3H), 1.84-1.69 (m, 4H), 1.44 (s, 3H), 1.37-1.29 (m, 4H), 0.65-0.58 (m, 2H), 0.47-0.41 (m, 2H).

Example 330: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methanol. 3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-carbaldehyde (Intermediate 149, 1.0 g, 5.7 mmol), tert-butyldimethyl((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane (Intermediate 43, 3.1 g, 8.6 mmol), P(1-nap)₃ (942 mg, 2.28 mmol), K₂CO₃ (3.94 g, 28.5 mmol), and 1,4-dioxane (30 mL) were added to a 100 mL round-bottomed flask. The mixture was sparged with N₂ for 5 minutes and then treated with PdCl₂ (202 mg, 1.14 mmol). The mixture was sparged with N₂ for another 5 minutes and then heated at 110° C. for 16 hours before it was allowed to cool to room temperature, poured into water (50 mL), and extracted with dichloromethane (50 mL×3). The aqueous portion was separated and extracted with ethyl acetate (3×200 mL). The extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=20:1 to 2:1, gradient elution) to afford the title compound (1.41 g, 50% yield). MS (ESI): mass calcd. for C₂₃H₃₃N₃O₂Si 411.23; m/z found, 412.2 [M+H]⁺.

Step B: Methyl 3-(34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate. 2,2,2-Trichloroacetonitrile (0.37 mL, 3.7 mmol) was added to a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methanol (1.0 g, 2.4 mmol), DBU (36 μL, 0.24 mmol), and DCE (20 mL) under Na. The resulting mixture was stirred at room temperature for 1 hour before treating with ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.69 g, 9.70 mmol) and TiCl₄ (1M in dichloromethane, 3.64 mL, 3.64 mmol). The mixture was stirred at room temperature for 1.5 hours before it was quenched with saturated aqueous NaHCO₃(60 mL) and extracted with dichloromethane (60 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (eluent: petroleum ether/ethyl acetate=1:1 to 0:1, gradient elution) to afford the title compound (550 mg, 41% yield). MS (ESI): mass calcd. for C₂₈H₄₁N₃O₃Si 495.29; m/z found, 496.3 [M+H]⁺.

Step C: Methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. TBAF (1 M in THF, 2.2 mL, 2.2 mmol) was added to a solution of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (550 mg, 1.11 mmol) and THF (10 mL). The resulting mixture was stirred at room temperature for 2 hours before it was quenched with H₂O (50 mL) and extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL×3), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (eluent: petroleum ether/ethyl acetate=5:1 to 0:1, gradient elution, then dichloromethane:methanol=10:1) to afford the title compound (380 mg, 71% yield). MS (ESI): mass calcd. for C₂₂H₂₇N₃O₃ 381.21; m/z found, 382.2 [M+H]⁺.

Step D: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate. SOCl₂ (0.57 mL, 7.8 mmol) was added to a solution of methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (300 mg, 0.786 mmol) and dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then was concentrated to dryness under reduced pressure to afford the title compound (320 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂ 399.17; m/z found, 400.2 [M+H]⁺.

Step E: Methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (320 mg, 0.8 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 192 mg, 0.799 mmol), K₂CO₃ (332 mg, 2.40 mmol), and CH₃CN (10 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was heated at 80° C. for 16 hours before it was allowed to cool to room temperature, quenched with H₂O (40 mL) and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (eluent: petroleum ether/ethyl acetate=1:1 to 0:1, gradient elution, then dichloromethane:methanol=10:1) to afford the title compound (390 mg, 68%) which was used without further purification. MS (ESI): mass calcd. for C₃₂H₃₇N₅O₅S 603.25; m/z found, 604.3 [M+H]⁺.

Step F: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. LiOH.H₂O (271 mg, 6.46 mmol) was added to a solution of methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (390 mg, 0.646 mmol), 1,4-dioxane (5 mL), and H₂O (5 mL). The resulting mixture was heated at 75° C. for 2 hours before being allowed to cool to room temperature, diluted with H₂O (30 mL), and extracted with ethyl acetate (30 mL×3). The pH of aqueous phase was adjusted to pH=6-7 with 1N HCl and the resulting mixture extracted with ethyl acetate (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (300 mg, 73% yield). MS (ESI): mass calcd. for C₃₁H₃₅N₅O₅S 589.24; m/z found, 590.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (br s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.62 (s, 1H), 7.16 (s, 2H), 7.09 (s, 1H), 6.62 (s, 1H), 4.73 (s, 1H), 3.58-3.53 (m, 7H), 2.65 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 1.23 (d, J=3.5 Hz, 6H), 0.88 (s, 2H), 0.50 (s, 2H).

Step G: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers was separated by chiral SFC (DAICEL CHIRALCEL OD-H 250 mm×30 mm, 5 μm, mobile phase: 35% to 35% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃) to afford two enantiomers. The first eluting isomer (89.6 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₅N₅O₅S 589.24; m/z found, 590.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=1.7 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.16 (s, 2H), 7.09 (s, 1H), 6.62 (s, 1H), 4.72 (s, 1H), 4.28-4.21 (m, 1H), 4.16-4.07 (m, 1H), 3.72-3.59 (m, 1H), 3.55 (s, 3H), 3.28-3.18 (m, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 1.22 (s, 6H), 0.92-0.84 (m, 2H), 0.55-0.47 (m, 2H).

Example 331: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer from the chiral separation described in Example 330 was further purified by preparative acidic HPLC (Boston Uni C18 150 mm×40 mm×5 μm column, mobile phase: 26% to 56% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to give the title compound (35.7 mg) and was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₅N₅O₅S 589.24; m/z found, 590.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.16 (s, 2H), 7.09 (s, 1H), 6.62 (s, 1H), 4.73 (s, 1H), 4.28-4.21 (m, 1H), 4.16-4.07 (m, 1H), 3.71-3.58 (m, 1H), 3.55 (s, 3H), 3.29-3.23 (m, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 1.27-1.19 (m, 6H), 0.93-0.84 (m, 2H), 0.55-0.45 (m, 2H).

Example 332: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: (4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. i-PrMgCl.LiCl (1.3 M in THF, 30 mL, 39 mmol) was added dropwise to a 250 mL three-necked round-bottomed flask containing a solution of 3-(difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 148, 10.0 g, 32.4 mmol) and THF (120 mL) that had been cooled to −10° C. This mixture was stirred at −10° C. for 1 hour before adding a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (Intermediate 147, 9.5 g, 36 mmol) and THF (30 mL) dropwise. The resulting mixture was stirred for 16 hours, gradually warming to room temperature, then was poured into saturated aqueous NH₄Cl (70 mL) and extracted with ethyl acetate (80 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 0:1, gradient elution) to give the title compound (7.5 g, 45% yield). MS (ESI): mass calcd. for C₂₂H₃₀F₂N₄O₂Si; 448.21 m/z found, 449.5 [M+H]⁺.

Step B: 7-((4-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. SOCl₂ (1.1 mL, 15 mmol) was added dropwise to a 100 mL three-necked round-bottomed flask containing a solution of (44(tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (6.0 g, 12 mmol), 2,6-di-tert-butylpyridine (6.8 mL, 29 mmol), and dichloromethane (80 mL) that had been cooled to 0° C. The resulting mixture was stirred at 0° C. for 40 minutes, basified with saturated aqueous NaHCO₃ to pH=8, poured into water (50 mL), and extracted with dichloromethane (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 1:1) to give the title compound (5 g, 86% yield). MS (ESI): mass calcd. for C₂₂H₂₉ClF₂N₄OSi; 466.18 m/z found, 467.4 [M+H]⁺.

Step C: tert-Butyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. InBr₃ (1.9 g, 5.4 mmol) was added to a 250 mL round-bottomed flask containing a solution of 7-((4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (5.0 g, 11 mmol), ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (Intermediate 271, 23.0 g, 106 mmol), and dichloromethane (80 mL) under Na. The resulting mixture was stirred at room temperature for 50 hours. The mixture was further treated with ((1-(tert-Butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (15 g, 69 mmol) and InBr₃ (1.0 g, 2.8 mmol). The resulting mixture was stirred at room temperature for 30 hours, then was poured into H₂O (50 mL) and extracted with dichloromethane (100 mL×3). These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=100:1 to 2:1) to afford the title compound (900 mg, 12% yield). MS (ESI): mass calcd. for C₃₀H₄₄F₂N₄O₃Si 574.32; m/z found, 575.2 [M+H]⁺.

Step D: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. TBAF (1 M in THF, 2.7 mL, 2.7 mmol) was added to a 30 mL round-bottomed flask containing a solution of tert-butyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (900 mg, 1.33 mmol) and THF (15 mL). The resulting mixture was stirred for 4 hours at room temperature, then was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (ethyl acetate) to give the title compound (450 mg, 71% yield). MS (ESI): mass calcd. for C₂₄H₃₀F₂N₄O₃ 460.23; m/z found, 461.1 [M+H]⁺. An alternative procedure to prepare the title compound, tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate, is described in the preparation of Intermediate 191.

Step E: tert-Butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. SOCl₂ (0.4 mL, 6 mmol) was added to a solution of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (450 mg, 0.977 mmol) and dichloromethane (8 mL) under Na. The resulting mixture was stirred at room temperature for 1 hour, then was concentrated to dryness under reduced pressure to give the title compound (480 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₄H₂₉ClF₂N₄O₂ 478.19; m/z found, 479.1 [M+H]⁺. An alternative procedure to prepare the title compound, tert-Butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate, is described in the preparation of Intermediate 192.

Step F: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. tert-Butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (200 mg, 0.42 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 90 mg, 0.38 mmol), K₂CO₃ (290 mg, 2.10 mmol), and CH₃CN (8 mL) were added to a 30 mL round-bottomed flask. The resulting mixture was stirred at 80° C. for 16 hours, then was allowed to cool to room temperature, poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (260 mg, 84% yield), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₄H₄₀F₂N₆O₅S 682.27; m/z found, 683.1 [M+H]⁺.

Step G: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. 4 N HCl in 1,4-dioxane (5 mL) was added to a solution of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (260 mg, 0.38 mmol), 1,4-dioxane (5 mL), and 3 drops of MeOH. The resulting mixture was stirred at room temperature for 16 hours, then an additional 4 N HCl in 1,4-dioxane (5 mL) was added. The mixture was stirred at room temperature for another 16 hours before concentrating to dryness under reduced pressure to give the title compound (300 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₅S 640.23; m/z found, 641.2 [M+H]⁺.

Step H: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. LiOH.H₂O (120 mg, 2.86 mmol) was added to a solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (300 mg, 0.468 mmol) and 1,4-dioxane: H₂O (1:1, 8 mL). The resulting mixture was stirred at 60° C. for 4 hours, then the pH was adjusted to pH=6 using 1 N HCl. The mixture was concentrated to dryness under reduced pressure and then purified by preparative acidic HPLC (Xtimate C18, 150×40 mm×10 μm column, mobile phase: 35% to 65% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to give the title compound (170 mg, 54% yield). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S 626.21; m/z found, 627.1 [M+H]⁺.

Step I: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers was separated by chiral SFC (DAICEL CHIRALPAK AS-H 250 mm×30 mm, 5 μm, mobile phase: 30% to 30% (v/v) supercritical CO₂ in EtOH and H₂O with 0.1% NH₃) to afford two enantiomers. The first eluting isomer (47.5 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S 626.21; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.36-8.33 (m, 2H), 8.32-8.30 (m, 1H), 8.04-8.02 (m, 1H), 7.85-7.56 (m, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.16 (s, 1H), 4.95 (s, 1H), 4.27-4.14 (m, 2H), 3.85-3.52 (m, 2H), 2.74 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 0.98-0.84 (m, 2H), 0.76-0.57 (m, 2H).

Example 333: (*R)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (45.5 mg) from the chiral separation described in Example 332 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S 626.21; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.36-8.33 (m, 2H), 8.33-8.30 (m, 1H), 8.04-8.01 (m, 1H), 7.84-7.57 (m, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.15 (s, 1H), 4.95 (s, 1H), 4.26-4.14 (m, 2H), 3.80-3.45 (m, 2H), 2.74 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H), 0.98-0.84 (m, 2H), 0.76-0.57 (m, 2H).

Example 334: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: (6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. i-PrMgCl.LiCl (1.3 M in THF, 25.4 mL, 33.0 mmol) was added dropwise to a 500 mL three-necked round-bottomed flask containing a 0° C. solution of 3-(difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 148, 6.8 g, 22 mmol) and THF (80 mL). The resulting mixture was stirred at 0° C. for 1 hour, then a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (Intermediate 57, 6.1 g, 23 mmol) and THF (20 mL) was added dropwise at 0° C. The resulting mixture was stirred for 16 hours with gradual warming to room temperature, then was poured into saturated aqueous NH₄Cl (50 mL) and extracted with ethyl acetate (60 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was triturated with petroleum ether/ethyl acetate (10:1, 20 mL) and the solid was isolated via filtration. The filter cake was washed with petroleum ether/ethyl acetate (10:1, 5 mL×3) and dried under reduced pressure to give the title compound (4.3 g, 42% yield). The filtrate was concentrated to dryness under reduced pressure and the material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 2:3) to give a second batch of the title compound (1.9 g, 5% yield). MS (ESI): mass calcd. for C₂₂H₃₀F₂N₄O₂Si 448.2; m/z found, 449.2 [M+H]⁺.

Step B: 7-((6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. SOCl₂ (0.57 mL, 7.8 mmol) was added dropwise to a 100 mL round-bottomed flask containing a 0° C. solution of (6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (2.7 g, 6.0 mmol), 2,6-di-tert-butylpyridine (3.4 mL, 15 mmol), and dichloromethane (30 mL). The resulting mixture was stirred at 0° C. for 40 minutes, then the pH of the solution was adjusted to pH=8-9 with saturated aqueous NaHCO₃, it was then poured into water (40 mL) and extracted with dichloromethane (50 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 1:1) to give the title compound (2.2 g, 73% yield). MS (ESI): mass calcd. for C₂₂H₂₉ClF₂N₄OS 466.2; m/z found, 467.2 [M+H]⁺.

Step C: Methyl 3-(64(tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. InBr₃ (228 mg, 0.643 mmol) was added to a 100 mL round-bottomed flask containing a solution of 7-((6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (1.0 g, 2.1 mmol), ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.87 g, 10.7 mmol) and dichloromethane (30 mL) under Na. The resulting mixture was stirred at room temperature for 48 hours, then was poured into water (30 mL) and extracted with dichloromethane (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 3:1) to give the title compound (460 mg, 37% yield). MS (ESI): mass calcd. for C₂₇H₃₈F₂N₄O₃Si 532.3; m/z found, 533.3 [M+H]⁺.

Step D: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. TBAF (1 M in THF, 1.74 mL, 1.74 mmol) was added to a 100 mL round-bottomed flask containing a solution of methyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (460 mg, 0.86 mmol) and THF (10 mL). The resulting mixture was stirred for 2 hours at room temperature, then was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (petroleum ether/ethyl acetate=1:0 to 1:1) to give the title compound (330 mg, 81% yield). MS (ESI): mass calcd. for C₂₁H₂₄F₂N₄O₃ 418.2; m/z found, 419.2 [M+H]⁺. An alternative procedure to prepare the title compound, methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate, is described in the preparation of Intermediate 195.

Step E: Methyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. SOCl₂ (0.17 mL, 2.3 mmol) was added to a 100 mL round-bottomed flask containing a solution of benzyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (330 mg, 0.79 mmol), and dichloromethane (5 mL). The resulting mixture was stirred for 0.5 hours at room temperature, then was concentrated to dryness under reduced pressure to give the title compound (350 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₁H₂₃ClF₂N₄O₂ 436.2; m/z found, 437.2 [M+H]⁺. An alternative procedure to prepare the title compound, methyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-2,2-dimethylpropanoate, is described in the preparation of Intermediate 196.

Step F: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. Methyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (300 mg, 0.69 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 168 mg, 0.699 mmol), K₂CO₃ (384 mg, 2.78 mmol), and CH₃CN (10 mL) were added to a 50 mL round-bottomed flask. The resulting mixture was stirred at 80° C. for 4 hours, then was allowed to cool to room temperature, poured into water (30 mL), and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (500 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₅S 640.2; m/z found, 642.4 [M+H]⁺.

Step G: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. (Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate) (480 mg, 0.65 mmol), NaOH (130 mg, 3.25 mmol), 1,4-dioxane (3 mL), and H₂O (3 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred at 65° C. for 16 hours, then was allowed to cool to room temperature, poured into water (10 mL), acidified with 1N HCl to pH=5-6, and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (DuraShell 150 mm×25 mm×5 μm column, mobile phase: 32% to 62% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to give the title compound (160 mg, 39% yield). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S 626.2; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.29 (d, J=7.3 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.85-7.56 (m, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 4.92 (s, 1H), 4.43-4.25 (m, 2H), 3.83-3.57 (m, 2H), 2.72 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), 1.30 (s, 3H), 1.23 (s, 3H), 1.07-0.93 (m, 2H), 0.86 (br s, 2H).

Step F: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers was separated by chiral SFC (DAICEL

CHIRALCEL OJ-H 250 mm×30 mm×5 μm, mobile phase: 40% to 40% (v/v) supercritical CO₂ in EtOH and H₂O with 0.1% NH₃) to afford two enantiomers. The first eluting isomer (76.4 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S 626.2; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.37-8.35 (m, 1H), 8.29 (d, J=7.2 Hz, 1H), 8.15-8.13 (m, 1H), 7.84-7.57 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.93 (s, 1H), 4.41-4.30 (m, 2H), 3.70 (s, 2H), 2.72 (s, 1H), 2.72 (s, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 1.30 (s, 3H), 1.22 (s, 3H), 1.04-0.95 (m, 2H), 0.89-0.80 (m, 2H).

Example 335: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-64(8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (71.9 mg) from the chiral separation described in Example 334 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₅S 626.2; m/z found, 627.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.36-8.34 (m, 1H), 8.28 (d, J=7.2 Hz, 1H), 8.14-8.12 (m, 1H), 7.84-7.56 (m, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.93 (s, 1H), 4.41-4.30 (m, 2H), 3.82-3.56 (m, 2H), 2.72 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), 1.29 (s, 3H), 1.22 (s, 3H), 1.03-0.95 (m, 2H), 0.89-0.80 (m, 2H).

Example 336: (*S)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Benzyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. SOCl₂ (1.85 mL, 25.5 mmol) was added to benzyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 71, 4.3 g, 8.4 mmol) and dichloromethane (40 mL). The resulting mixture was stirred for 1 hour at room temperature. The mixture was combined with another batch of the same compound and concentrated to dryness under reduced pressure to give the title compound (5.2 g). MS (ESI): mass calcd. for C₂₄H₂₇ClF₃N₃O₂ 529.2; m/z found, 530.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J=7.3 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 7.22-7.18 (m, 1H), 7.14-7.02 (m, 6H), 5.06 (d, J=12.3 Hz, 1H), 4.89 (d, J=12.3 Hz, 1H), 4.73 (s, 1H), 4.70 (s, 2H), 2.56 (s, 3H), 2.31 (s, 3H), 1.35 (s, 3H), 1.29 (s, 3H).

Step B: tert-Butyl 2′-(5-(3-(benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-2-methylbenzyl)-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. Benzyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (600 mg, 1.13 mmol), tert-butyl 2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 150, 418 mg, 1.13 mmol), K₂CO₃ (630 mg, 4.56 mmol), and CH₃CN (10 mL) were added to a 30 mL tube. The resulting mixture was stirred at 80° C. for 6 hours, then was allowed to cool to room temperature, poured into water (30 mL), and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (950 mg, 92% yield). MS (ESI): mass calcd. for C₄₄H₄₉F₃N₆O₇S 862.31; m/z found, 863.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.54 (dd, J=2.0, 5.0 Hz, 1H), 8.26 (d, J=7.3 Hz, 1H), 8.15 (dd, J=1.9, 7.7 Hz, 1H), 7.44 (dd, J=4.9, 7.7 Hz, 1H), 7.24 (d, J=7.3 Hz, 2H), 7.08 (s, 2H), 7.05-7.00 (m, 5H), 5.07 (d, J=12.0 Hz, 1H), 4.88 (d, J=12.3 Hz, 1H), 4.73 (s, 1H), 4.47-4.32 (m, 2H), 3.66 (d, J=11.8 Hz, 4H), 3.21 (d, J=9.5 Hz, 2H), 2.51 (s, 3H), 2.14 (s, 3H), 1.67-1.55 (m, 2H), 1.53-1.43 (m, 2H), 1.36 (s, 9H), 1.36 (br s, 3H), 1.30 (s, 3H).

Step C: 3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. (tert-Butyl 2′-(5-(3-(benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-2-methylbenzyl)-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide) (950 mg, 1.10 mmol), MeOH (20 mL), and wet Pd/C (100 mg, 5 wt. %) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred under an atmosphere of H₂ (15 psi, balloon) at room temperature for 16 hours. The suspension was filtered through a pad diatomaceous earth, such as of Celite® and the pad washed with ethyl acetate (10 mL×2). The filtrate was concentrated to dryness under reduced pressure to give the title compound (850 mg, 92% yield). MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S 772.29; m/z found, 773.2 [M+H]⁺.

Step D: (*S)-3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The mixture of 3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers was separated by chiral SFC (DAICEL CHIRALPAK IC 250 mm×30 mm, 5 μm, mobile phase: 45% to 45% (v/v) supercritical CO₂ in EtOH and H₂O with 0.1% NH₃) to afford two enantiomers. The first eluting isomer (330 mg) was designated (*S): MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S 772.29; m/z found, 773.4 [M+H]⁺.

Step E: (*S)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. ((*S)-3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid) (310 mg, 0.401 mmol), 4 N HCl in 1,4-dioxane (10 mL, 40 mmol), and 1,4-dioxane (5 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred for 16 hours at room temperature before concentrating to dryness under reduced pressure. The material was purified by chiral SFC (DAICEL CHIRALCEL OD-H 250 mm×30 mm×5 μm column, mobile phase: 30% to 30% (v/v) EtOH and H₂O with 0.1% NH₃) to give the title compound (50.3 mg, 18% yield). MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S 672.23; m/z found, 673.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.52-8.49 (m, 1H), 8.33-8.29 (m, 1H), 8.26 (d, J=7.2 Hz, 1H), 7.47-7.44 (m, 1H), 7.43-7.38 (m, 1H), 7.35 (s, 1H), 7.28-7.23 (m, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.14 (s, 1H), 4.63-4.50 (m, 2H), 3.66-3.52 (m, 2H), 3.44-3.34 (m, 2H), 3.30-2.97 (m, 2H), 2.83 (s, 3H), 2.19 (s, 3H), 2.05-1.50 (m, 4H), 1.42 (s, 3H), 1.23 (s, 3H).

Example 337: (*R)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (*R)-3-(3-((1-(tert-butoxycarbonyl)-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The second eluting isomer (290 mg) from the chiral separation described in Example 336, Step D was designated (*R): MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S 772.29; m/z found, 773.4 [M+H]⁺.

Step B: (*R)-3-(3-((1′,1′-Dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. (*R)-3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (290 mg, 0.375 mmol), 4 N HCl in 1,4-dioxane (10 mL, 40 mmol), and 1,4-dioxane (5 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred for 16 hours at room temperature, then was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (DuraShell 150 mm×25 mm×5 μm column, mobile phase: 15% to 45% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to give the title compound (117.1 mg, 45% yield). MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S 672.23; m/z found, 673.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.52-8.49 (m, 1H), 8.34-8.23 (m, 3H), 7.47-7.39 (m, 2H), 7.35 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.12 (s, 1H), 4.63-4.50 (m, 2H), 3.69-3.51 (m, 2H), 3.45-3.35 (m, 2H), 3.26-3.07 (m, 2H), 2.82 (s, 3H), 2.19 (s, 3H), 2.00-1.62 (m, 4H), 1.42 (s, 3H), 1.24 (s, 3H).

Example 338: (*S)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: 3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (700 mg, 93% yield) was prepared using analogous conditions as described in Example 336 where tert-Butyl 2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 151) was used instead of tert-Butyl 2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₅H₃₉F₃N₆O₇S 744.26; m/z found, 745.2 [M+H]⁺.

Step B: (*S)-3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The mixture of 3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers was separated by chiral SFC (DAICEL CHIRALPAK IG 250 mm×30 mm, 10 mobile phase: 40% to 40% (v/v) supercritical CO₂ in IPA and H₂O with 0.1% NH₃). The first eluting isomer was designated (*S) and was further purified by preparative acidic HPLC (DuraShell, 150 mm×25 mm×5 μm column, mobile phase: 40% to 70% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to give the title compound (300 mg, 43%). MS (ESI): mass calcd. for C₃₅H₃₉F₃N₆O₇S 744.26; m/z found, 745.2 [M+H]⁺.

Step C: (*S)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. (*S)-3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)) propanoic acid (300 mg, 0.403 mmol) and formic acid (10 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred for 16 hours at room temperature, then was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (DuraShell 150 mm×25 mm×5 μm column mobile phase: 20% to 50% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to give the title compound (137 mg, 47% yield). MS (ESI): mass calcd. for C₃₅H₃₉F₃N₆O₇S 644.20; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.50 (m, 1H), 8.30-8.26 (m, 1H), 8.23 (br s, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.41-7.34 (m, 3H), 7.13-7.08 (m, 2H), 4.85-4.73 (m, 2H), 4.16-4.07 (m, 2H), 3.98 (s, 2H), 3.96-3.86 (m, 2H), 3.14-3.05 (m, 1H), 2.85 (s, 3H), 2.21 (s, 3H), 1.40 (s, 3H), 1.33 (s, 3H).

Example 339: (*R)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (*R)-3-(3-((1-(tert-butoxycarbonyl)-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The second eluting isomer (390 mg) from the chiral separation described in Example 338, Step B was designated (*R): MS (ESI): mass calcd. for C₃₅H₃₉F₃N₆O₇S 744.26; m/z found, 745.2 [M+H]⁺.

Step B: (*R)-3-(3-((1′,1′-Dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. (*R)-3-(3-((1-(tert-Butoxycarbonyl)-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (370 mg, 0.497 mmol) and formic acid (10 mL) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred for 16 hours at room temperature, then was concentrated to dryness under reduced pressure to give the title compound (244.8 mg, 68% yield). MS (ESI): mass calcd. for C₃₅H₃₉F₃N₆O₇S 644.20; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.61-8.57 (m, 1H), 8.34-8.30 (m, 1H), 8.27 (d, J=7.2 Hz, 1H), 8.16 (br s, 1H), 7.59-7.51 (m, 2H), 7.46 (s, 1H), 7.20-7.16 (m, 1H), 7.13-7.09 (m, 1H), 4.94 (s, 1H), 4.64 (d, J=14.0 Hz, 1H), 4.28 (d, J=13.6 Hz, 1H), 4.13 (s, 2H), 4.03 (d, J=11.6 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.61 (d, J=11.6 Hz, 1H), 2.78 (s, 3H), 2.20 (s, 3H), 1.40 (s, 3H), 1.28 (s, 3H).

Example 340: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: 3-(3-((1-(tert-Butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (600 mg, 38% yield) was prepared using analogous conditions as described in Example 336 where tert-butyl 8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 152) was used instead of tert-butyl 2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₄H₄₅F₃N₆O₇S 786.30; m/z found, 787.3 [M+H]⁺.

Step B: (*S)-3-(3-((1-(tert-Butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The mixture of 3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers was separated by chiral SFC (DAICEL CHIRALPAK IC 250 mm×50 mm, 5 mobile phase: 45% to 45% (v/v) supercritical CO₂ in MeOH and H₂O with 0.1% NH₃). The first eluting isomer (220 mg) was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₅F₃N₆O₇S 786.30; m/z found, 787.3 [M+H]⁺.

Step C: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. 4N HCl in 1,4-dioxane (5 mL) was added to a solution of (*S)-3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (220 mg, 0.280 mmol) and 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 1.5 hours, then was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (Agela ASB 150 mm×25 mm×5 μm column, mobile phase: 33% to 63% (v/v) CH₃CN and H₂O with 0.05% HCl) to give the title compound (100.6 mg, 48% yield). MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₅S 686.25; m/z found, 687.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36-9.25 (m, 1H), 9.15-9.01 (m, 1H), 8.47 (d, J=7.0 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.33 (d, J=7.3 Hz, 1H), 7.29-7.25 (m, 1H), 7.19-7.14 (m, 1H), 7.13-7.09 (m, 1H), 4.81 (s, 1H), 4.50-4.34 (m, 2H), 3.56-3.38 (m, 2H), 3.31-3.20 (m, 2H), 3.19-3.09 (m, 2H), 2.66 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H), 1.93-1.79 (m, 4H), 1.32 (s, 3H), 1.27 (s, 3H).

Example 341: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (*R)-3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The second eluting isomer (220 mg) from the chiral separation described in Example 340, Step B was designated (*R): MS (ESI): RT=0.904 min, mass calcd. For C₃₄H₄₅F₃N₆O₇S 786.30 m/z found 787.3 [M+H]⁺.

Step B: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. 4N HCl in 1,4-dioxane (5 mL) was added to a solution of (*R)-3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (220 mg, 0.280 mmol) and 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 1.5 hours, then was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (Venusil ASB Phenyl, 250 mm×50 mm×10 μm column, mobile phase: 30% to 60% (v/v) CH₃CN and H₂O with 0.05% HCl) to give the title compound (110 mg, 53% yield). MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₅S 686.25; m/z found, 687.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.43-9.33 (m, 1H), 9.22-9.09 (m, 1H), 8.47 (d, J=7.0 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.28-7.25 (m, 1H), 7.18-7.14 (m, 1H), 7.13-7.09 (m, 1H), 4.81 (s, 1H), 4.48-4.41 (m, 2H), 3.77-3.60 (m, 2H), 3.32-3.20 (m, 2H), 3.18-3.09 (m, 2H), 2.66 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H), 1.92-1.82 (m, 4H), 1.32 (s, 3H), 1.27 (s, 3H).

Example 342: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: tert-Butyl 2′-(5-(3-(benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-2-methylbenzyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. Benzyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 336, Step A, 1.0 g, 1.9 mmol), K₂CO₃ (1.0 g, 7.2 mmol), and MeCN (20 mL) were added to a 50 mL round-bottomed flask. The resulting mixture was stirred for 10 mins at room temperature and then treated with tert-butyl 8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 153, 671 mg, 1.89 mmol). The resulting mixture was stirred for 16 hours at 80° C., then was poured into water (20 mL) and extracted with ethyl acetate (30 mL×3). These extractions resulted in several organic solvent fractions which were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The material was combined with another batch of the same compound and purified by FCC (petroleum ether/ethyl acetate=1:0 to 3:7) to give the title compound (1.5 g). MS (ESI): mass calcd. for C₄₃H₄₇F₃N₆O₇S 848.93; m/z found, 849.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=1.8 Hz, 1H), 8.22 (d, J=7.1 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.22 (d, J=7.3 Hz, 2H), 7.13-7.08 (m, 2H), 7.06-6.95 (m, 5H), 5.07 (d, J=12.1 Hz, 1H), 4.88 (d, J=12.1 Hz, 1H), 4.71 (s, 1H), 4.37-4.28 (m, 1H), 4.22 (d, J=16.3 Hz, 1H), 3.86-3.69 (m, 6H), 2.51 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H), 1.36 (s, 9H), 1.35 (s, 3H), 1.30 (s, 3H).

Step B: 3-(3-((1-(tert-Butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. tert-Butyl 2′4543-(benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-2-methylbenzyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (1.3 g, 1.5 mmol), MeOH (10 mL), and wet Pd/C (100 mg, 10 wt. %) were added to a 50 mL hydrogenation bottle. The resulting mixture was stirred under H₂ (50 psi) at room temperature for 1.5 hours. The suspension was filtered through a pad diatomaceous earth, such as of Celite® and the pad washed with MeOH (10 mL×3). The filtrate was concentrated to dryness under reduced pressure. The material was combined with another batch of the same compound to give the title product (1.1 g). MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₇S 758.27; m/z found, 759.3 [M+H]⁺.

Step C: (*S)-3-(3-((1-(tert-Butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The mixture of 3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers was separated by chiral SFC (DAICEL CHIRALPAK IC 250 mm×30 mm, 10 mobile phase: 30% to 30% (v/v) supercritical CO₂ in MeOH and H₂O with 0.1% NH₃). The first eluting isomer (500 mg) was designated (*S): MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₇S 758.27; m/z found, 759.3 [M+H]⁺.

Step D: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. HCOOH (6 mL) and (*R)-3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (500 mg, 0.659 mmol) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred at room temperature for 16 hours, then was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (DuraShell, 150 mm×25 mm×5 μm column, mobile phase: 20% to 50% (v/v) CH₃CN and H₂O with 0.225% HCOOH) to give the title compound (350 mg, 80% yield). MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₇S 658.27; m/z found, 659.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.17-7.14 (m, 1H), 7.11-7.08 (m, 1H), 4.65 (s, 1H), 4.53 (d, J=13.5 Hz, 1H), 4.12 (d, J=13.7 Hz, 1H), 4.01-3.96 (m, 2H), 3.80 (s, 4H), 2.65 (s, 3H), 2.38 (s, 3H), 2.18 (s, 3H), 1.22 (s, 3H), 1.12 (s, 3H).

Example 343: (*R)-2,2-Dimethyl-3-(4-methyl-3 48′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (*R)-3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The second eluting isomer (550 mg) from the chiral separation described in Example 342, Step C was designated (*R): MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₇S 758.27; m/z found, 759.3 [M+H]⁺.

Step B: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. HCOOH (6 mL) and (*R)-3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (530 mg, 0.698 mmol) were added to a 100 mL round-bottomed flask. The resulting mixture was stirred at room temperature for 16 hours, then was concentrated to dryness under reduced pressure. The material was purified by preparative acidic HPLC (DuraShell, 150 mm×25 mm×5 μm column, mobile phase: 20% to 50% (v/v) CH₃CN and H₂O with 0.2% HCOOH), and then further purified by preparative HPLC (Xtimate C18, 150 mm×40 mm×10 μm column, mobile phase: 23% to 53% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to give the title compound (180 mg, 36% yield). MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₇S 658.27; m/z found, 659.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.45 (d, J=1.8 Hz, 1H), 8.35 (d, J=7.3 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.93 (s, 1H), 7.35 (s, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.11 (d, J=1.0 Hz, 1H), 4.63 (s, 1H), 4.55 (d, J=13.2 Hz, 1H), 4.13-4.08 (m, 1H), 3.95 (s, 3H), 3.80 (s, 3H), 2.66 (s, 3H), 2.39 (s, 3H), 2.33 (s, 1H), 2.19 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H).

Example 344: (*R)-3-(3-((7′-(3-((2-(2-Aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (E)-tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)acrylate. tert-Butyl acrylate (477 mg, 3.72 mmol), Pd(OAc)₂ (32.1 mg, 0.143 mmol), 2-(di-tert-butylphosphino)biphenyl (85.5 mg, 0.287 mmol), and Et₃N (580 mg, 5.73 mmol) were added to a solution of 7′-bromo-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (1.00 g, 2.86 mmol, Intermediate 124) and DMF (18 mL). The resulting mixture was sparged with N₂ for 5 minutes and then stirred while heating at 120° C. for 3 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with sat. NH₄Cl (7 mL) and the resultant mixture was extracted with ethyl acetate (2×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 1:5, gradient) to afford the title compound (805 mg, 71%) as a yellow solid. MS (ESI): mass calcd. for C₁₈H₂₄N₂O₆S 396.1 m/z found 396.9 [M+H]⁺.

Step B: tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate. (E)-tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)acrylate (805 mg, 2.03 mmol), MeOH (10 mL), and dry Pd/C (200 mg, 10 wt. %, 0.189 mmol) were added to 75 mL hydrogenation vessel. The resultant mixture was stirred at room temperature for 16 hours under H₂ (50 psi). The suspension was filtered through a pad diatomaceous earth, such as of Celite® and the pad was washed with MeOH (20 mL). The filtrate was concentrated to dryness under reduced pressure to give the product. This was combined with an additional batch of tert-Butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate and purified by flash column chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 1:5, gradient) to afford the title compound (781 mg). MS (ESI): mass calcd. for C₁₈H₂₆N₂O₆S 398.2 m/z found 399.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.60-8.10 (m, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 3.81 (t, J=9.8 Hz, 2H), 3.57 (d, J=10.8 Hz, 2H), 3.47 (s, 2H), 2.97 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H), 1.72-1.46 (m, 4H), 1.34 (s, 9H).

Step C: (*R)-Methyl 3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DIAD (2.33 g, 11.5 mmol) was added to a solution of (*R)-methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (2.5 g, 5.7 mmol, Intermediate 141), tert-butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoate (2.8 g, 6.9 mmol), PPh₃ (3.02 g, 11.5 mmol), and THF (30 mL). The resultant mixture was stirred at room temperature for 3 hours before concentrating to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 1:3, gradient) to afford the title compound (2.06 g, 37%). MS (ESI): mass calcd. for C₄₀H₄₈F₃N₅O₈S 815.3 m/z found 816.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.1 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25-7.16 (m, 3H), 7.16-7.09 (m, 1H), 4.80 (s, 1H), 4.54-4.24 (m, 2H), 3.76 (d, J=9.1 Hz, 2H), 3.55-3.40 (m, 6H), 2.99 (t, J=6.9 Hz, 2H), 2.76-2.59 (m, 5H), 2.15 (s, 3H), 2.07 (s, 1H), 1.52-1.40 (m, 4H), 1.36 (s, 12H), 1.29 (s, 3H).

Step D: (*R)-3-(2′-(5-(3-Methoxy-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid. 4 N HCl in 1,4-dioxane (10 mL) was added to a solution of (*R)-methyl 3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.20 g, 1.47 mmol) and 1,4-dioxane (5 mL) at room-temperature. The mixture was stirred at room-temperature for 1 hour before concentrating to dryness under reduced pressure to afford the title compound (1.10 g, 98%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₆H₄₀F₃N₅O₈S 759.3 m/z found 760.2 [M+H]⁺.

Step E: (*R)-Methyl 3-(3-((7′-(2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazatetradecan-14-yl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. HATU (286 mg, 0.752 mmol) was added to a solution of (*R)-3-(2′-(5-(3-methoxy-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid (1.1 g, 0.58 mmol), tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (130 mg, 0.636 mmol), DIPEA (374 mg, 2.89 mmol), and DMF (15 mL) at 0° C. The resultant mixture was stirred at room-temperature for 16 hours. This was combined with an additional batch of (*R)-Methyl 3-(3-((7′-(2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazatetradecan-14-yl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate, diluted with H₂O (15 mL) and extracted with ethyl acetate (2×). These extractions resulted in several fractions which were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 0:10, gradient) to afford the title compound (1.2 g). MS (ESI): mass calcd. for C₄₅H₅₈F₃N₇O₁₀S 945.4 m/z found 946.4 [M+H]⁺.

Step F: (*R)-3-(3-((7′-(2,2-Dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazatetradecan-14-yl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)propanoic acid. (*R)-Methyl 3-(3-((7′-(2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazatetradecan-14-yl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (500 mg, 0.529 mmol) was added to a solution of LiOH.H₂O (127 mg, 5.30 mmol), THF (3 mL), MeOH (3 mL), and H₂O (3 mL). The resultant mixture was stirred at 65° C. for 16 hours before cooling to room-temperature, adjusting the pH to 6-7 with 1 N HCl, and extracting with ethyl acetate (2×). These extractions resulted in several fractions which were combined and concentrated to dryness under reduced pressure to afford the product (467 mg, 95%). MS (ESI): mass calcd. for C₄₄H₅₆F₃N₇O₁₀S 931.4 m/z found 932.7 [M+H]⁺.

Step G: (*R)-3-(3-((7′-(3-((2-(2-Aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. 4 N HCl in 1,4-dioxane (3 mL) was added to a solution of (*R)-3-(3-((7′-(2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazatetradecan-14-yl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (250 mg, 0.268 mmol) and 1,4-dioxane (3 mL) at room-temperature. The resultant mixture was stirred at room-temperature for 1 hour. This was combined with an additional batch of (*R)-3-(3-((7′-(3-((2-(2-Aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid and concentrated to dryness under reduced pressure to give the product, which was further purified by reverse phase preparative HPLC (stationary phase: Phenomenex Synergi C18 150×30 mm, 4 μm column; eluent: 17% to 37% (v/v) CH₃CN and aqueous HCl (0.006 N)) to afford pure product. The product was suspended in water (10 mL), extracted with ethyl acetate (3×). These extractions resulted in several fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (8.7 mg, 4%). MS (ESI): mass calcd. for C₃₉H₄₈F₃N₇O₈S 831.3 m/z found 832.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.42 (d, J=7.1 Hz, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.42-7.32 (m, 1H), 7.29 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 6.17 (d, J=7.3 Hz, 1H), 5.26 (s, 1H), 4.74 (s, 1H), 4.41-4.31 (m, 2H), 3.64-3.43 (m, 8H), 3.42 (d, J=4.9 Hz, 3H), 3.25 (d, J=4.9 Hz, 2H), 3.07-2.93 (m, 4H), 2.79 (t, J=6.9 Hz, 2H), 2.66 (s, 2H), 2.56-2.52 (m, 2H), 2.18 (s, 3H), 1.53 (s, 2H), 1.26 (d, J=15.4 Hz, 6H).

Example 345: (*S)-3-(3-((7′-(3-((2-(2-aminoethoxy)ethyl)amino)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (2.04 g) was prepared using analogous conditions as described in Example 344 where (*S)-methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 143) was used instead of (*R)-methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 141) in step C. MS (ESI): mass calcd. for C₄₀H₄₈F₃N₅O₈S 815.3 m/z found 816.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.3 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H),7.29 (d, J=7.8 Hz, 1H), 7.25-7.17 (m, 3H), 7.15-7.09 (m, 1H), 4.85-4.72 (m, 1H), 4.52-4.21 (m, 2H), 3.84-3.69 (m, 2H), 3.60-3.34 (m, 6H), 2.99 (t, J=7.0 Hz, 2H), 2.72-2.59 (m, 5H), 2.16 (s, 3H), 2.07 (s, 1H), 1.54-1.39 (m, 4H), 1.36 (s, 12H), 1.29 (s, 3H).

Example 346: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methanol. A mixture of 3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-carbaldehyde (Intermediate 149, 1.0 g, 5.7 mmol), tert-butyldimethyl((2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane (3.1 g, 8.6 mmol), P(1-nap)₃ (942 mg, 2.28 mmol), K₂CO₃ (3.94 g, 28.5 mmol), and 1,4-dioxane (30 mL) was sparged with N₂ for 5 minutes and then treated with PdCl₂ (202 mg, 1.14 mmol). The mixture was sparged with N₂ for another 5 minutes and then stirred and heated at 110° C. for 16 hours before cooling to room-temperature, pouring it into water (50 mL), and extracting with dichloromethane (3×). These extractions resulted in several fractions that were dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 20:1 to 2:1, gradient) to afford the title compound (1.41 g, 50%). MS (ESI): mass calcd. for C₂₃H₃₃N₃O₂Si 411.2, m/z found 412.2 [M+H]⁺.

Step B: tert-Butyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate. 2,2,2-Trichloroacetonitrile (682 μL, 6.80 mmol) was added to a solution of (34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methanol (1.4 g, 3.4 mmol), DBU (101 μL, 0.676 mmol), and DCE (30 mL) under Na. The resultant mixture was stirred at room-temperature for 1 hour before treating with ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (8.1 g, 37 mmol) and BF₃.OEt₂ (558 μL, 4.42 mmol). The mixture was then stirred at room-temperature for another 1.5 hours before quenching with water (60 mL) and extracting with dichloromethane (3×). These extractions resulted in several fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 20:1 to 1:1, gradient) to afford the title compound (600 mg, 27%). MS (ESI): mass calcd. for C₃₁H₄₇N₃O₃Si 537.3, m/z found 538.3 [M+H]⁺.

Step C: tert-Butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. TBAF (2.23 mL, 1 M in THF, 2.23 mmol) was added to a solution of tert-butyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (600 mg, 1.12 mmol) and THF (10 mL). The resultant mixture was stirred at room-temperature for 2 hours before quenching with H₂O (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were washed with brine (3×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 1:1, gradient) to afford the title compound (222 mg, 45%). MS (ESI): mass calcd. for C₂₅H₃₃N₃O₃ 423.3, m/z found 424.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (s, 1H), 7.25 (s, 1H), 7.08-7.02 (m, 2H), 6.58 (s, 1H), 5.05-4.97 (m, 1H), 4.59 (s, 1H), 4.42-4.36 (m, 2H), 3.59 (s, 3H), 2.61 (s, 3H), 2.16 (s, 3H), 1.21 (s, 3H), 1.18 (s, 3H), 1.07 (s, 9H).

Step D: tert-Butyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate. SOCl₂ (0.16 mL, 2.2 mmol) was added to a solution consisting of tert-butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (190 mg, 0.449 mmol) and dichloromethane (5 mL). The resultant mixture was stirred at room-temperature for 1 hour before concentrating to dryness under reduced pressure to afford the title compound (200 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₅H₃₂ClN₃O₂ 411.2, m/z found 442.2 [M+H]⁺.

Step E: tert-Butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A mixture of tert-Butyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (200 mg), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (180 mg, 0.453 mmol, Intermediate 145), K₂CO₃ (188 mg, 1.36 mmol), and CH₃CN (10 mL) was stirred at 90° C. for 16 hours before cooling to room-temperature, pouring it into H₂O (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (360 mg, 100%), which was used in the next step without further purification. MS mass calcd. for C₄₃H₅₈N₆O₇S 802.4, m/z found 803.5 [M+H]⁺.

Step F: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. 4 N HCl in 1,4-dioxane (10 mL) was added drop-wise to tert-butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (360 mg), and 1,4-dioxane (3 mL). The resultant mixture was stirred at room-temperature for 16 hours before concentrating to dryness under reduced pressure to give the product, which was purified by reverse phase preparative HPLC (stationary phase: Waters Xbridge Prep OBD C18 150 mm×30 mm×10 μm column; eluent: 20% to 50% (v/v) CH₃CN and H₂O with 10 mM NH₄HCO₃) to afford the title compound (150 mg, 45%). MS (ESI): mass calcd. for C₃₉H₅₀N₆O₇S 746.4, m/z found 747.3 [M+H]⁺.

Step G: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2(pyrrolidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid. The mixture of 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK IG 250 mm×30 mm, 10 μm, mobile phase: 50% to 50% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The first eluting isomer (36 mg, 24%) was designated (*S). MS (ESI): mass calcd. for C₃₉H₅₀N₆O₇S 746.4, m/z found 747.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 7.13 (s, 2H), 6.63 (s, 1H), 4.73 (s, 1H), 4.47-4.34 (m, 4H), 3.84-3.73 (m, 2H), 3.58 (s, 3H), 3.55-3.50 (m, 6H), 2.84-2.78 (m, 2H), 2.63 (s, 3H), 2.55-2.53 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.71-1.63 (m, 4H), 1.56-1.42 (m, 4H), 1.23 (d, J=6.4 Hz, 6H).

Example 347: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 346) were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK IG 250 mm×30 mm, 10 μm, mobile phase: 50% to 50% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The second eluting isomer (38 mg, 25%) was designated (*R). MS (ESI): mass calcd. for C₃₉H₅₀N₆O₇S 746.4, m/z found 747.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (s, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 7.13 (s, 2H), 6.64 (s, 1H), 4.74 (s, 1H), 4.45-4.35 (m, 4H), 3.85-3.74 (m, 2H), 3.59 (s, 3H), 3.56-3.53 (m, 6H), 2.85-2.79 (m, 2H), 2.63 (s, 3H), 2.56-2.54 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.70-1.64 (m, 4H), 1.57-1.43 (m, 4H), 1.23 (d, J=6.1 Hz, 6H).

Example 348: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid

Step A: tert-Butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. tert-Butyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (200 mg, Example 346, step D), 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (182 mg, 0.442 mmol, Intermediate 72), K₂CO₃ (188 mg, 1.36 mmol), and CH₃CN (10 mL) were mixed and stirred at 80° C. for 16 hours before cooling to room-temperature, quenching with water (80 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the compound (290 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₄H₆₀N₆O₇S 816.4, m/z found 817.5 [M+H]⁺.

Step B: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid. 4 N HCl in 1,4-dioxane (6 mL) was added drop-wise to tert-butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (280 mg, 0.34 mmol) and 1,4-dioxane (5 mL). The resultant mixture was stirred at room-temperature for 16 hours before concentrating to dryness under reduced pressure to give the product, which was purified by preparative HPLC (stationary phase: Waters Xbridge Prep OBD C18 150×30 mm×5 μm column; eluent: 20% to 40% (v/v) CH₃CN and H₂O with 10 mM NH₄HCO₃) to afford the title compound (120 mg, 46%). MS (ESI): mass calcd. for C₄₀H₅₂N₆O₇S 760.4, m/z found 761.3 [M+H]⁺.

Step C: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid. The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid isomers were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK IG 250 mm×30 mm, 10 mobile phase: 50% to 50% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The first eluting isomer (29 mg, 23%) was designated (*S). MS (ESI): mass calcd. for C₄₀H₅₂N₆O₇S 760.4, m/z found 761.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (s, 1H), 7.61 (s, 1H), 7.25 (s, 1H), 7.14 (s, 2H), 6.64 (s, 1H), 4.74 (s, 1H), 4.47-4.34 (m, 4H), 3.86-3.74 (m, 2H), 3.60 (s, 3H), 3.58-3.38 (m, 6H), 3.31-3.25 (m, 2H), 2.78-2.69 (m, 2H), 2.64 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.58-1.33 (m, 10H), 1.26 (s, 6H).

Example 349: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 348) were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK IG 250 mm×30 mm, 10 μm, mobile phase: 50% to 50% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The second eluting isomer (33 mg, 27%) was designated (*R). MS (ESI): mass calcd. for C₄₀H₅₂N₆O₇S 760.4, m/z found 761.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (s, 1H), 7.58 (s, 1H), 7.21 (s, 1H), 7.11 (s, 2H), 6.61 (s, 1H), 4.71 (s, 1H), 4.46-4.32 (m, 4H), 3.82-3.70 (m, 2H), 3.57 (s, 3H), 3.55-3.45 (m, 6H), 3.15-3.02 (m, 2H), 2.83-2.70 (m, 2H), 2.61 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.55-1.35 (m, 10H), 1.23 (s, 6H).

Example 350: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid

Step A: tert-Butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A mixture of tert-Butyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (210 mg, Example 346, step D), 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (175 mg, 0.476 mmol, Intermediate 136), K₂CO₃ (197 mg, 1.43 mmol), and CH₃CN (10 mL) was stirred at 90° C. for 16 hours before cooling to room-temperature. The suspension was filtered through a pad diatomaceous earth, such as of Celite® and the pad washed with ethyl acetate (50 mL). The filtrate was concentrated to dryness under reduced pressure to afford the title product (360 mg, 0.47 mmol), which was used next step without further purification. MS (ESI): mass calcd. for C₄₂H₅₆N₆O₆S 772.4, m/z found 773.5 [M+H]⁺.

Step B: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. 4 N HCl in 1,4-dioxane (6 mL) was added drop-wise to a solution of tert-butyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (360 mg, 0.47 mmol) and 1,4-dioxane (2 mL). The resultant mixture was stirred at room-temperature for 16 hours before concentrating to dryness under reduced pressure. The residue was purified by preparative HPLC using a Phenomenex Gemini-NX C18 150 mm×30 mm×5 μm column (eluent: 30% to 50% (v/v) CH₃CN and H₂O with 0.04% NH₃H₂O and 10 mM NH₄HCO₃) to afford the title compound (100 mg, 30%). MS (ESI): mass calcd. for C₃₄H₄₈N₆O₆S 716.3, m/z found 717.4 [M+H]⁺.

Step C: (*S)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid. The mixture of 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK IG 250 mm×30 mm, 10 μm; mobile phase: 45% to 45% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The first eluting isomer (25 mg, 25%) was designated (*S). MS (ESI): mass calcd. for C₃₄H₄₈N₆O₆S 716.3, m/z found 717.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.62 (s, 1H), 7.17 (s, 2H), 7.07 (s, 1H), 6.62 (s, 1H), 4.73 (s, 1H), 4.52-4.39 (m, 2H), 4.27-4.17 (m, 1H), 4.14-4.06 (m, 1H), 3.64-3.59 (m, 1H), 3.55 (s, 3H), 3.30-3.23 (m, 7H), 2.65 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 1.64-1.35 (m, 6H), 1.25-1.22 (m, 6H), 0.97-0.89 (m, 2H), 0.61-0.42 (m, 2H).

Example 351: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidine-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer, (24 mg, 24%), from the chiral separation described in Example 350 was designated (*R). MS (ESI): mass calcd. for C₃₄H₄₈N₆O₆S 716.3, m/z found 717.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 7.58 (s, 1H), 7.14 (s, 2H), 7.04 (s, 1H), 6.59 (s, 1H), 4.69 (s, 1H), 4.47-4.35 (m, 2H), 4.23-4.14 (m, 1H), 4.11-4.03 (m, 1H), 3.61-3.56 (m, 1H), 3.51 (s, 3H), 3.25-3.17 (m, 7H), 2.61 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.59-1.37 (m, 6H), 1.21-1.19 (m, 6H), 0.93-0.88 (m, 2H), 0.54-0.41 (m, 2H).

Example 352: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Methyl 3-(34(tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate. 2,2,2-trichloroacetonitrile (0.37 mL, 3.7 mmol) was added to a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)methanol (1.0 g, 2.4 mmol, Example 346, Step A), DBU (36 μL, 0.24 mmol), and DCE (20 mL) under Na. The resultant mixture was stirred at room-temperature for 1 hour before treating with ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.69 g, 9.70 mmol) and TiCl₄ (3.64 mL, 1 M in dichloromethane, 3.64 mmol). The mixture was stirred at room-temperature for another 1.5 hours before quenching with sat. NaHCO₃(60 mL) and extracting with dichloromethane (3×). These extractions resulted in several fractions that were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:1 to 0:1, gradient) to afford the title compound (550 mg, 41%). MS (ESI): mass calcd. for C₂₄H₄₁N₃O₃Si 495.3, m/z found 496.3 [M+H]⁺.

Step B: Methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. TBAF (2.2 mL, 1 M in THF, 2.2 mmol) was added to a solution consisting of methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (550 mg, 1.11 mmol) and THF (10 mL). The resultant mixture was stirred at room-temperature for 2 hours before quenching with H₂O (50 mL) and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (3×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 5:1 to 0:1 (gradient), then dichloromethane/methanol 10:1, isocratic) to afford the title compound (380 mg, 71%). MS (ESI): mass calcd. for C₂₂H₂₇N₃O₃ 381.2, m/z found 382.2 [M+H]⁺.

Step C: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate. SOCl₂ (0.57 mL, 7.8 mmol) was added to a solution consisting of methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (300 mg, 0.786 mmol) and dichloromethane (10 mL). The resultant mixture was stirred at room-temperature for 1 hour before concentrating to dryness under reduced pressure to afford the title compound (320 mg), which was used next step without further purification. MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂ 399.2, m/z found 400.2 [M+H]⁺.

Step D: Methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethylpropanoate (160 mg), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (141 mg, 0.399 mmol, Intermediate 137), K₂CO₃ (166 mg, 1.20 mmol), and CH₃CN (10 mL) were mixed and stirred at 80° C. for 16 hours before cooling to room-temperature. The resulting suspension was filtered through a pad diatomaceous earth, such as of Celite® and the pad washed with ethyl acetate (50 mL). The filtrate was concentrated to dryness under reduced pressure to give the product (300 mg), which was used next step without further purification. MS (ESI): mass calcd. for C₃₄H₄₈N₆O₆S 716.3, m/z found 717.3 [M+H]⁺.

Step E: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. LiOH.H₂O (176 mg, 4.19 mmol) was added to a solution consisting of methyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (300 mg, 0.418 mmol), 1,4-dioxane (5 mL), and H₂O (5 mL). The resulting mixture was then stirred at 75° C. for 1 hour before cooling to room-temperature, diluting with H₂O (30 mL), and washing with ethyl acetate (3×). The aqueous phase was adjusted to pH=6 to 7 with 1 N HCl and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (stationary phase: Waters Xbridge C18, 150 mm×50 mm×5 μm column; eluent: 20% to 50% (v/v) CH₃CN and H₂O with 10 mM NH₄HCO₃) to afford the title compound (130 mg, 43%). MS (ESI): mass calcd. for C₃₇H₄₆N₆O₆S 702.3, m/z found 703.3 [M+H]⁺.

Step F: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK IG 250 mm×30 mm, 10 μm; mobile phase: 50% to 50% (v/v) supercritical CO₂ in i-PrOH and H₂O with 0.1% NH₃). The first eluting isomer (42 mg, 30%) was designated (*S). MS (ESI): mass calcd. for C₃₇H₄₆N₆O₆S 702.3, m/z found 703.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (s, 1H), 7.57 (s, 1H), 7.13 (s, 2H), 7.03 (s, 1H), 6.58 (s, 1H), 4.68 (s, 1H), 4.39-4.31 (m, 2H), 4.23-4.14 (m, 1H), 4.10-4.02 (m, 1H), 3.58-3.56 (m, 1H), 3.51 (s, 3H), 3.28-3.28 (m, 1H), 2.87-2.80 (m, 2H), 2.61 (s, 3H), 2.59-2.54 (m, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 1.69-1.63 (m, 4H), 1.18 (s, 6H), 0.92-0.87 (m, 2H), 0.54-0.39 (m, 2H).

Example 353: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazine-6-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)-ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′-(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (36 mg, 27%) from the chiral separation described in Example 352 was designated (*R). MS (ESI): mass calcd. for C₃₇H₄₆N₆O₆S 702.3, m/z found 703.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s, 1H), 7.61 (s, 1H), 7.16 (s, 2H), 7.07 (s, 1H), 6.62 (s, 1H), 4.72 (s, 1H), 4.43-4.37 (m, 2H), 4.26-4.19 (m, 1H), 4.14-4.06 (m, 1H), 3.70-3.67 (m, 1H), 3.55 (s, 3H), 3.33-3.31 (m, 1H), 2.97-2.88 (m, 2H), 2.71-2.61 (m, 7H), 2.26 (s, 3H), 2.16 (s, 3H), 1.76-1.68 (m, 4H), 1.22 (s, 6H), 0.97-0.88 (m, 2H), 0.56-0.43 (m, 2H).

Example 354: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: 6-chloro-3-methylpyridin-2-yl)methanol. Borane tetrahydrofuran complex (219 mL, 1 M in THF, 219 mmol) was added drop-wise to a solution consisting of 6-chloro-3-methylpicolinic acid (25.0 g, 146 mmol) and THF (200 mL) at 0° C. The mixture was stirred at 50° C. for 3 hours before cooling to 0° C. followed by drop-wise addition of MeOH (300 mL) at 0° C. The reaction was stirred for an additional 1 hour with gradual warming to room-temperature. The mixture was concentrated to dryness under reduced pressure to afford the title compound (22.5 g, 98%), which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 4.50 (s, 2H), 2.30 (s, 3H).

Step B: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloro-3-methylpyridine. TBSCl (25.9 g, 172 mmol) was added to a solution of (6-chloro-3-methylpyridin-2-yl)methanol (22.5 g, 143 mmol), imidazole (19.5 g, 286 mmol), and dichloromethane (400 mL) 0° C. The mixture was stirred for 2.5 hours with gradual warming to room-temperature. The suspension was isolated via filtration. The filter cake was washed with ethyl acetate (3×), and the filtrate concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 9:1, gradient) to afford title compound (22.9 g, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 4.70 (s, 2H), 2.32 (s, 3H), 0.85-0.84 (m, 9H), 0.04 (s, 6H).

Step C: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-6-vinylpyridine. Pd(dppf)Cl₂ (2.5 g, 3.4 mmol) was added to a solution consisting of 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-3-methylpyridine (22.9 g, 84.2 mmol), potassium trifluoro(vinyl)borate (22.8 g, 170 mmol), K₃PO₄ (54.2 g, 255 mmol), 1,4-dioxane (300 mL), and H₂O (60 mL) under N₂. The mixture was stirred at 100° C. for 16 hours, cooled to room-temperature, poured into water (50 mL), and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 5:1, gradient) to afford the title product (17.3 g, 78%). ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 6.79 (dd, J=10.8, 17.6 Hz, 1H), 6.14 (dd, J=1.1, 17.4 Hz, 1H), 5.40 (dd, J=1.1, 10.9 Hz, 1H), 4.84 (s, 2H), 2.40 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H).

Step D: 6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde. K₂OsO₄.2H₂O (1.2 g, 3.3 mmol) was added to a solution consisting of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-6-vinylpyridine (17.3 g, 65.7 mmol), 1,4-dioxane (250 mL), and H₂O (250 mL). The resultant mixture was treated with NaIO₄ (41.9 g, 196 mmol) in portions slowly and then stirred at room-temperature for 6 hours. The resultant suspension was isolated via filtration and the filter cake washed with ethyl acetate (3×). The filtrate was separated and the aqueous layer extracted with ethyl acetate (2×). These extractions resulted in several fractions that were combined, washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 9:1, gradient) to afford the title compound (7.3 g, 31%). MS (ESI): mass calcd. for C₁₄H₂₃NO₂Si 265.2 m/z found 266.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 7.86-7.77 (m, 2H), 4.86 (s, 2H), 2.46 (s, 3H), 0.86 (s, 9H), 0.06 (s, 6H).

Step E: (6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. i-PrMgCl.LiCl (25.4 mL, 1.3 M in THF, 33.0 mmol) was added drop-wise to a solution of 3-(difluoromethyl)-7-iodo-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (6.8 g, 22 mmol, Intermediate 148) and THF (80 mL) at 0° C. The resultant mixture was stirred at 0° C. for 1 hour and then treated with a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpicolinaldehyde (6.1 g, 23 mmol) and THF (20 mL) by drop-wise addition at 0° C. The mixture was stirred for 16 hours with gradual warming to room-temperature, poured into sat. NH₄Cl (50 mL), and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was triturated with petroleum ether: ethyl acetate (10:1, 20 mL and the suspension isolated via filtration. The filter cake was washed with petroleum ether/ethyl acetate (10:1, 3×) before drying under reduced pressure to afford the title compound (4.3 g, 44%). The filtrate was concentrated to dryness under reduced pressure to give the product, which was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 2:3, gradient) to afford the second batch of title compound (1.9 g, 19%). MS (ESI): mass calcd. for C₂₂H₃₀F₂N₄O₂Si 448.2 m/z found 449.2 [M+H]⁺.

Step F: 7-((6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine. SOCl₂ (0.57 mL, 7.8 mmol) was added drop-wise to a solution consisting of (6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (2.7 g, 6.0 mmol), 2,6-di-tert-butylpyridine (3.4 mL, 15 mmol), and dichloromethane (30 mL) at 0° C. The resulting mixture was stirred at 0° C. for 40 minutes before adjusting the pH with aq. NaHCO₃ to pH=8-9, poured into water (40 mL), and extracted with dichloromethane (3×). These extraction resulted in several fractions that were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 1:1, gradient) to afford the title compound (2.2 g, 73%). MS (ESI): mass calcd. for C₂₂H₂₉ClF₂N₄OS 466.2 m/z found 467.2 [M+H]⁺.

Step G: tert-Butyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. InBr₃ (501 mg, 1.41 mmmol) was added to a solution of 7-((6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)chloromethyl)-3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine (2.2 g, 4.7 mmol), ((1-(tert-butoxy)-2-methylprop-1-en-1-yl)oxy)trimethylsilane (10.2 g, 47.1 mmol), and dichloromethane (40 mL) under Na. The resultant mixture was stirred at room-temperature for 5 days, poured it into water (30 mL) and extracted with dichloromethane (3×). These extractions resulted in several fractions that were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 3:2, gradient) to afford the title compound (1.3 g, 48%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₀H₄₄F₂N₄O₃S 574.3 m/z found 575.3 [M+H]⁺.

Step H: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. TBAF (4.4 mL, 1 M in THF, 4.4 mmol) was added to a solution of tert-butyl 3-(6-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (1.3 g) and THF (10 mL). The resultant mixture was stirred for 2 hours at room-temperature, poured into water (30 mL) and extracted with ethyl acetate (3×). These extractions resulted in several fraction that were combined, washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 1:0 to 1:1, gradient) to afford the title compound (350 mg, 32%). MS (ESI): mass calcd. for C₂₄H₃₀F₂N₄O₃ 460.2 m/z found 461.2 [M+H]⁺. An alternative procedure to prepare the title compound, tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate, is described in the preparation of Intermediate 193.

Step I: tert-Butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. SOCl₂ (0.18 mL, 2.5 mmol) was added to a solution consisting of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (350 mg, 0.760 mmol) and dichloromethane (4 mL). The resultant mixture was stirred for 0.5 hours at room-temperature before concentrating to dryness under reduced pressure to afford the title compound (320 mg, 88%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₄H₂₉ClF₂N₄O₂ 478.2 m/z found 479.2 [M+H]⁺. An alternative procedure to prepare the title compound, tert-butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate, is described in the preparation of Intermediate 194.

Step J: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. tert-Butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (230 mg, 0.480 mmol), 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (200 mg, 0.486 mmol, Intermediate 72), K₂CO₃ (403 mg, 2.92 mmol), and CH₃CN (5 mL) were mixed and stirred at 80° C. for 6 hours. The reaction was cooled to room-temperature, poured into water (20 mL), and extracted with ethyl acetate (3×). These extractions resulted in several organic fractions that were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (320 mg, 78%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₃H₅₇F₂N₇O₇S 853.4 m/z found 854.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=7.3 Hz, 1H), 7.89 (s, 1H), 7.83-7.65 (m, 1H), 7.63-7.56 (m, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 4.90 (s, 1H), 4.63-4.46 (m, 2H), 4.43 (t, J=6.0 Hz, 2H), 3.92-3.81 (m, 2H), 3.66 (d, J=19.8 Hz, 4H), 2.75 (s, 3H), 2.68 (d, J=6.2 Hz, 2H), 2.45 (br s, 6H), 2.25 (s, 3H), 2.16 (s, 3H), 1.62 (d, J=7.5 Hz, 4H), 1.52-1.47 (m, 4H), 1.37 (s, 3H), 1.24 (s, 3H), 1.16 (s, 9H).

Step K: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. (tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate) (320 mg, 0.375 mmol), 4 N HCl in 1,4-dioxane (30 mL, 120 mmol), and 1,4-dioxane (5 mL) were mixed and stirred for 24 hours at room-temperature before concentrating to dryness under reduced pressure. The residue was purified by reverse-phase preparative HPLC (stationary phase: Agela ASB 150 mm×25 mm×5 μm column; eluent: 25% to 50% (v/v) CH₃CN and H₂O with 0.05% HCl) to afford the title compound (200 mg, 67%). MS (ESI): mass calcd. for C₃₉H₄₉F₂N₇O₇S 797.3 m/z found 798.4 [M+H]⁺.

Step L: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK AD-H 250 mm×30 mm×5 μm; eluent: 25% to 25% (v/v) in EtOH and H₂O with 0.1% NH₃). The first eluting isomer (60 mg, 30%) was designated (*S). MS (ESI): mass calcd. for C₃₉H₄₉F₂N₇O₇S 797.3 m/z found 798.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=7.2 Hz, 1H), 7.90 (s, 1H), 7.71 (t, J=52 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 4.95 (s, 1H), 4.55 (s, 2H), 4.49-4.42 (m, 2H), 3.91-3.80 (m, 2H), 3.77-3.67 (m, 2H), 3.64-3.59 (m, 2H), 3.31-3.00 (m, 6H), 2.75 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 1.76-1.64 (m, 2H), 1.63-1.56 (m, 2H), 1.55-1.46 (m, 4H), 1.42-1.35 (m, 2H), 1.33 (s, 3H), 1.29 (s, 3H).

Example 355: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers that were separated as described in Example 354, Step L also provided the second eluting isomer that was designated (*R) but required further purification by reverse phase HPLC (stationary phase: Xtimate C18 150 mm×25 mm×5 μm; eluent: 15% to 45% (v/v) in water and ACN with 0.225% HCOOH) to afford the title compound (29 mg, 14%). MS (ESI): mass calcd. for C₃₉H₄₉F₂N₇O₇S 797.3 m/z found 798.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=7.3 Hz, 1H), 7.89 (s, 1H), 7.71 (t, J=52 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.59-4.50 (m, 2H), 4.44 (t, J=6.0 Hz, 2H), 3.86 (t, J=11.6 Hz, 2H), 3.78-3.68 (m, 2H), 3.67-3.56 (m, 4H), 3.15-2.91 (m, 2H), 2.75 (s, 3H), 2.70 (t, J=6.2 Hz, 2H), 2.24 (s, 3H), 2.16 (s, 3H), 1.78-1.65 (m, 2H), 1.63-1.56 (m, 2H), 1.52-1.47 (m, 4H), 1.40-1.35 (m, 2H), 1.33 (s, 3H), 1.29 (s, 3H).

Example 356: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-64(8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. tert-Butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (185 mg, 0.386 mmol), 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (140 mg, 0.381 mmol, Intermediate 136), K₂CO₃ (320 mg, 2.32 mmol), and CH₃CN (5 mL) were mixed and stirred at 80° C. for 6 hours. The reaction was cooled to room-temperature, poured into water (20 mL), and extracted with ethyl acetate (3×). These extractions resulted in the isolation of several fractions that were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (320 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₁H₅₃F₂N₇O₆S 809.4 m/z found 810.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=7.3 Hz, 1H), 7.99 (s, 1H), 7.84-7.57 (m, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.19 (t, J=7.6 Hz, 2H), 4.87 (s, 1H), 4.38 (t, J=6.0 Hz, 2H), 4.35-4.25 (m, 2H), 2.72 (s, 3H), 2.66 (t, J=6.0 Hz, 2H), 2.43 (br s, 4H), 2.34 (s, 3H), 2.17 (s, 3H), 1.52-1.34 (m, 8H), 1.31 (s, 3H), 1.17 (s, 3H), 1.12 (s, 9H), 1.08-1.03 (m, 2H), 0.85 (br s, 2H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. (tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate) (300 mg, 0.370 mmol), 4 N HCl in 1,4-dioxane (15 mL, 60 mmol), and 1,4-dioxane (5 mL) were mixed and stirred at room-temperature for 16 hours before concentrating to dryness under reduced pressure to give the product, which was purified by reverse phase preparative HPLC (stationary phase: Xtimate C18 150 mm×40 mm×10 μm column; eluent: 15% to 45% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to afford title compound (200 mg, 72%). MS (ESI): mass calcd. for C₃₇H₄₅F₂N₇O₆S 753.3 m/z found 754.4 [M+H]⁺.

Step C: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers were separated by chiral SFC (stationary phase: DAICEL CHIRALPAK AD-H 250 mm×30 mm×5 μm; eluent: 25% to 25% (v/v) in EtOH and H₂O with 0.1% NH₃). The first eluting isomer (78 mg, 38%) was designated (*S). MS (ESI): mass calcd. for C₃₇H₄₅F₂N₇O₆S 753.3 m/z found 754.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=7.2 Hz, 1H), 7.99 (s, 1H), 7.7 (t, J=52 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.28-7.19 (m, 2H), 4.92 (s, 1H), 4.41-4.36 (m, 2H), 4.36-4.26 (m, 2H), 3.73-3.62 (m, 2H), 2.72 (s, 3H), 2.70-2.64 (m, 2H), 2.48-2.40 (m, 4H), 2.33 (s, 3H), 2.18 (s, 3H), 1.52-1.44 (m, 4H), 1.41-1.34 (m, 2H), 1.30 (s, 3H), 1.22 (s, 3H), 1.09-0.98 (m, 2H), 0.84 (s, 2H).

Example 357: (*R)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers were that separated by chiral SFC as described in Example 356, Step C also provided a second eluting isomer (74 mg, 35%) that was designated (*R). MS (ESI): mass calcd. for C₃₇H₄₅F₂N₇O₆S 753.3 m/z found 754.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=7.2 Hz, 1H), 7.99 (s, 1H), 7.7 (t, J=52 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.28-7.19 (m, 2H), 4.92 (s, 1H), 4.41-4.36 (m, 2H), 4.36-4.26 (m, 2H), 3.73-3.62 (m, 2H), 2.72 (s, 3H), 2.70-2.64 (m, 2H), 2.48-2.40 (m, 4H), 2.33 (s, 3H), 2.18 (s, 3H), 1.52-1.44 (m, 4H), 1.41-1.34 (m, 2H), 1.30 (s, 3H), 1.22 (s, 3H), 1.09-0.98 (m, 2H), 0.84 (s, 2H).

Example 358: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-64(8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. tert-Butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (221 mg, 0.461 mmol), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (163 mg, 0.461 mmol, Intermediate 137), K₂CO₃ (383 mg, 2.77 mmol), and CH₃CN (5 mL) mixed and stirred at 80° C. for 6 hours. The reaction was cooled to room-temperature, poured into water (20 mL), and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the title compound (350 mg, 95%), which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₀H₅₁F₂N₇O₆S 795.4 m/z found 796.4 [M+H]⁺.

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. (tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate) (350 mg, 0.440 mmol), 4 N HCl in 1,4-dioxane (18 mL, 72 mmol), and 1,4-dioxane (5 mL) were mixed and stirred for 16 hours at room-temperature before concentrating to dryness under reduced pressure. The residue was purified by reverse-phase preparative HPLC (stationary phase: Xtimate C18 150 mm×40 mm×10 μm column; eluent: 13% to 43% (v/v) CH₃CN and H₂O with 0.2% HCOOH) to afford the title compound (190 mg, 58%). MS (ESI): mass calcd. for C₃₆H₄₃F₂N₇O₆S 739.3 m/z found 740.4 [M+H]⁺.

Step C: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b]1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid. The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers were separated by chiral SFC (stationary phase: Phenomenex-Amylose-1 250 mm×30 mm×5 μm column; eluent: 30% to 30% (v/v) EtOH with 0.1% % NH₃/H₂O). The first eluting isomer (59 mg, 30%) was designated (*S). MS (ESI): mass calcd. for C₃₆H₄₃F₂N₇O₆S 739.3 m/z found 740.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=7.2 Hz, 1H), 7.99 (s, 1H), 7.66 (t, J=51.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.28-7.19 (m, 2H), 4.92 (s, 1H), 4.40 (t, J=5.6 Hz, 2H), 4.37-4.27 (m, 2H), 3.70-3.65 (m, 2H), 2.85 (t, J=5.4 Hz, 2H), 2.71 (s, 3H), 2.61-2.56 (m, 4H), 2.33 (s, 3H), 2.19 (s, 3H), 1.72-1.66 (m, 4H), 1.30 (s, 3H), 1.21 (s, 3H), 1.08-0.98 (m, 2H), 0.83 (s, 2H).

Example 359: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers were separated by chiral SFC as described in Example 358, Step C also provided a second eluting isomer (69 mg, 33%) that was designated (*R). MS (ESI): mass calcd. for C₃₆H₄₃F₂N₇O₆S 739.3 m/z found 740.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d, J=7.3 Hz, 1H), 8.00 (s, 1H), 7.84-7.56 (m, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.28-7.19 (m, 2H), 4.92 (s, 1H), 4.41 (t, J=5.5 Hz, 2H), 4.37-4.28 (m, 2H), 3.70-3.65 (m, 2H), 2.90 (t, J=5.5 Hz, 2H), 2.71 (s, 3H), 2.67-2.62 (m, 4H), 2.33 (s, 3H), 2.19 (s, 3H), 1.75-1.67 (m, 4H), 1.30 (s, 3H), 1.22 (s, 3H), 1.08-0.99 (m, 2H), 0.89-0.79 (m, 2H).

Example 360: (*R)-3-(3-((7′-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid

The title compound (78 mg, 48%) was prepared using analogous conditions as described in Example 126 where 7′-((2-(4,4-difluoropiperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 125) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) and benzyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 139) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 17) in step A. MS (ESI): mass calcd. for C₃₉H₄₅F₅N₆O₇S, 836.3; m/z found, 837.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.02 (s, 1H), 7.26 (dd, J=7.6, 2.8 Hz, 2H), 7.21 (d, J=1.8 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.82-6.76 (m, 1H), 4.81 (s, 1H), 4.50-4.29 (m, 4H), 3.79-3.65 (m, 3H), 3.46 (s, 3H), 2.79 (s, 1H), 2.65-2.52 (m, 6H), 2.19 (s, 4H), 1.96 (s, 3H), 1.52 (d, J=15.1 Hz, 2H), 1.30 (d, J=22.7 Hz, 9H).

Example 361: (*R)-3-(3-((7′-(((1R,3R)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (97 mg, 55%) was prepared using analogous conditions as described in Example 114 where 3-aminocyclobutan-1-ol was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3-((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S, 772.3; m/z found, 773.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.47 (d, J=1.0 Hz, 1H), 7.29-7.20 (m, 2H), 7.19 (d, J=2.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.78 (d, J=6.2 Hz, 1H), 5.06 (d, J=5.6 Hz, 1H), 4.79 (s, 1H), 4.37 (d, J=15.1 Hz, 1H), 4.24 (d, J=15.1 Hz, 1H), 3.99-3.70 (m, 4H), 3.42 (d, J=10.6 Hz, 1H), 3.35-3.21 (m, 3H), 2.67-2.57 (m, 5H), 2.19 (s, 3H), 2.06 (s, 3H), 1.93-1.75 (m, 2H), 1.50-1.42 (m, 2H), 1.35-1.17 (m, 8H).

Example 362: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((R-1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 364) were separated by chiral SFC (Stationary phase: Whelk-O1 (S,S) 5 μm 25*21.2 mm, Mobile phase: 68% CO₂, 32% (70% i-PrOH/DCM with 0.3% i-PrNH₂). The firsteluting isomer (21 mg) was designated *R/*R: MS (ESI): mass calcd. for C₄₀H₅₀F₃N₇O₇S, 829.3; m/z found, 830.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.95 (d, J=7.2 Hz, 1H), 7.59 (s, 1H), 7.23-7.17 (m, 2H), 7.04 (dd, J=8.9, 7.0 Hz, 2H), 4.82 (s, 1H), 4.43 (d, J=14.3 Hz, 1H), 4.34 (d, J=14.5 Hz, 1H), 3.98-3.55 (m, 8H), 3.48-3.40 (m, 2H), 2.75-2.50 (m, 6H), 2.19-2.05 (m, 6H), 1.65-1.52 (m, 5H), 1.49-1.15 (m, 13H).

Example 363: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((S-1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 364) were separated by chiral SFC as described in Example 362, provided a second eluting isomer (20 mg) that was designated *R/*S: MS (ESI): mass calcd. for C₄₀H₅₀F₃N₇O₇S, 829.3; m/z found, 830.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 7.93 (d, J=7.3 Hz, 1H), 7.60 (s, 1H), 7.18-7.11 (m, 2H), 7.09-7.05 (m, 1H), 7.03 (d, J=7.9 Hz, 1H), 4.81 (s, 1H), 4.46-4.29 (m, 2H), 3.90-3.80 (m, 6H), 3.55 (d, J=11.1 Hz, 2H), 3.49-3.42 (m, 2H), 2.77-2.60 (m, 6H), 2.18 (d, J=18.4 Hz, 6H), 1.66-1.48 (m, 5H), 1.41-1.14 (m, 13H).

Example 364: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′ 4(1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (65 mg, 57%) was prepared using analogous conditions as described in Example 114 where 1-morpholinopropan-2-amine was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₄₀H₅₀F₃N₇O₇S, 829.3; m/z found, 830.3 [M+H]⁺.

Example 365: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (142 mg, 58%) was prepared using analogous conditions as described in Example 114 where 2-morpholinoethan-1-amine was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₃₉H₄₈F₃N₇O₇S, 815.3; m/z found, 816.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.49-7.45 (m, 1H), 7.29-7.17 (m, 3H), 7.13 (d, J=7.9 Hz, 1H), 6.75 (t, J=5.6 Hz, 1H), 4.79 (s, 1H), 4.37 (d, J=15.2 Hz, 1H), 4.27 (d, J=15.2 Hz, 1H), 3.82-3.72 (m, 2H), 3.60-3.54 (m, 4H), 3.46-3.40 (m, 4H), 3.38-3.20 (m, 1H), 2.64 (s, 3H), 2.50-2.40 (m, 6H), 2.19 (s, 3H), 2.03 (s, 3H), 1.51-1.43 (m, 2H), 1.38-1.20 (m, 9H).

Example 366: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*R)-4-(2-((2′-(5-(3-methoxy-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-8′-methyl-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazxepin]-7′-yl)amino)ethyl)piperazine-1-carboxylate. The title compound (244 mg, 97%) was prepared using analogous conditions as described in Example 114 where tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₄₅H₅₉F₃N₈O₈S, 928.4; m/z found, 929.3 [M+H]⁺.

Step B: Methyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperazin-1-yl)ethyl)amino-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. tert-butyl (*R)-4-(2-((2′-(5-(3-methoxy-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-8′-methyl-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazxepin]-7′-yl)amino)ethyl)piperazine-1-carboxylate (244 mg, 0.26 mmol) was dissolved in a 50/50 solution of TFA/DCM (2 mL) and stirred at r.t. for 1 h. The solvent was removed under reduced pressure yielding 275 mg (99%) of the title compound as the bis-TFA-salt which was used in the next step without purification. MS (ESI): mass calcd. for C₄₀H₅₃F₃N₈O₆S. 2TFA, 828.4; m/z found, 829.3 [M+H]⁺.

Step C: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethyl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (113 mg, 52%) was prepared using analogous conditions as described in Example 114 where methyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperazin-1-yl)ethyl)amino-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of methyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperazin-1-yl)ethyl)amino-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₉H₄₉F₃N₈O₆S, 814.3; m/z found, 815.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=7.2 Hz, 1H), 7.48 (d, J=1.0 Hz, 1H), 7.33 (d, J=7.3 Hz, 1H), 7.25-7.23 (m, 1H), 7.20-7.14 (m, 1H), 7.11 (d, J=7.9 Hz, 1H), 6.72 (t, J=5.7 Hz, 1H), 4.79 (s, 1H), 4.35 (d, J=14.7 Hz, 1H), 4.24 (d, J=14.8 Hz, 1H), 3.82-3.72 (m, 2H), 3.60-3.10 (m, 6H), 2.79-2.70 (m, 4H), 2.62 (s, 3H), 2.45-2.35 (m, 7H), 2.19 (s, 3H), 2.03 (s, 3H), 1.52-1.47 (m, 2H), 1.30-1.17 (m, 8H).

Example 367: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(0)-1-(pyrrolidine-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (93 mg, 79%) was prepared using analogous conditions as described in Example 114 where (S)-1-(pyrrolidine-1-yl)propan-2-amine was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₄₀H₅₀F₃N₇O₆S, 813.3; m/z found, 814.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J=7.2 Hz, 1H), 7.47 (s, 1H), 7.29-7.21 (m, 2H), 7.18 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 6.36 (d, J=7.7 Hz, 1H), 4.79 (s, 1H), 4.39-4.35 (m, 1H), 4.31-4.19 (m, 2H), 3.83-3.74 (m, 2H), 3.45-3.27 (m, 3H), 2.64 (s, 3H), 2.58-2.37 (m, 6H), 2.19 (s, 3H), 2.04 (s, 3H), 1.69-1.63 (m, 4H), 1.52-1.42 (m, 2H), 1.36-1.11 (m, 12H).

Example 368: (*R)-3-(3-((1′,1′-Dioxido-7′-((2-(piperazin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*R)-4-(2-((2′-(5-(3-(benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran]4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)oxy)ethyl)piperazine-1-carboxylate. The title compound (417 mg, 108%) was prepared using analogous conditions as described in Example 126 where tert-butyl 4-(2-((1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)oxy)ethyl)piperazine-1-carboxylate (Intermediate 126) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) and benzyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 139) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. MS (ESI): mass calcd. for C₅₀H₆₀F₃N₇O₉S, 991.4; m/z found, 992.3 [M+H]⁺.

Step B: (*R)-3-(3-((7′-((2-(4-(tert-Butoxycarbonyl)piperazine-1-yl ethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran]4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (367 mg, 97%) was prepared using analogous conditions as described in Example 126 where tert-butyl (*R)-4-(2-((2′-(5-(3-(benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran]4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)oxy)ethyl)piperazine-1-carboxylate was used instead of benzyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-(4-methyl-3-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethyoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]propanoate in step B. MS (ESI): mass calcd. for C₄₃H₅₄F₃N₇O₉S, 901.4; m/z found, 902.3 [M+H]⁺.

Step C: (*R)-3-(3-((1′,1′-Dioxido-7′-((2-(piperazin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid. (*R)-3-(3-((7′-((2-(4-(tert-butoxycarbonyl)piperazine-1-yl ethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran]4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (367 mg, 0.41 mmol) was dissolved in a 1:1 mixture of TFA/DCM (2.0 mL) and stirred at r.t. for 1 h. The solvent was then removed under reduced pressure and the resulting residue purified by reverse phase HPLC (eluent: MeCN/H₂O (with 20 mM NH₄OH), 10:90 to 70:30, gradient) to afford the title compound (213 mg, 65%). MS (ESI): mass calcd. for C₃₄H₄₆F₃N₇O₇S, 801.3; m/z found, 802.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J=7.2 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.19 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.79 (s, 1H), 4.47-4.27 (m, 4H), 3.74 (q, J=10.5 Hz, 2H), 3.60-3.10 (m, 5H), 2.75-2.60 (m, 9H), 2.47-2.35 (s, 4H), 2.18 (s, 3H), 1.55-1.47 (m, 2H), 1.42-1.30 (m, 2H), 1.25 (s, 3H), 1.22 (s, 3H).

Example 369: (*R)-2,2-Dimethyl-3-(4-methyl-3-(8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-4-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid

The title compound (115 mg, 65%) was prepared using analogous conditions as described in Example 368 where tert-butyl hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′yl)oxy)ethyl)piperidine-1-carboxylate (Intermediate 133) was used instead of tert-butyl 4-(2-((1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)oxy)ethyl)piperazine-1-carboxylate (Intermediate 126) in step A. MS (ESI): mass calcd. for C₄₀H₄₉F₃N₆O₇S, 814.3; m/z found, 815.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29 (d, J=7.2 Hz, 1H), 7.79 (s, 1H), 7.29 (d, J=7.4 Hz, 1H), 7.21-7.13 (m, 1H), 7.09-6.99 (m, 2H), 4.69 (s, 1H), 4.39-4.22 (m, 4H), 3.73-3.62 (m, 2H), 3.45-3.32 (m, 2H), 2.96 (d, J=11.4 Hz, 2H), 2.57-2.49 (m, 5H), 2.17-2.00 (m, 6H), 1.68-1.34 (m, 8H), 1.33-1.00 (m, 12H).

Example 370: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate. The title compound (645 mg, 44%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. MS (ESI): mass calcd. for C₄₃H₅₅F₃N₆O₇S, 856.4; m/z found, 857.3 [M+H]⁺.

Step B: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid. To a 25-mL round bottom flask fitted with a reflux condenser was added tert-butyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate (80 mg 0.09 mmol), DCM (3.0 mL) and TFA (0.75 mL). The mixture was heated to 50° C. for 3 h then cooled, and solvent removed under reduced pressure. The residue was purified by reverse phase HPLC (eluent: MeCN/H₂O (with 20 mM NH₄OH), 10:90 to 70:30, gradient) to afford the title compound (55 mg, 74%). MS (ESI): mass calcd. for C₃₉H₄₇F₃N₆O₇S, 800.3; m/z found, 801.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=7.2 Hz, 1H), 7.86 (s, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.30-7.25 (m, 1H), 7.14-7.04 (m, 2H), 4.81 (s, 1H), 4.47-4.23 (m, 4H), 3.79-3.70 (m, 2H), 3.45-3.20 (m, 4H), 2.81 (t, J=5.9 Hz, 2H), 2.62-2.43 (m, 5H), 2.19 (s, 3H), 2.15 (s, 3H), 1.77-1.61 (m, 4H), 1.47 (d, J=13.8 Hz, 2H), 1.40-1.22 (m, 4H), 1.16 (s, 3H), 1.10 (s, 3H).

Example 371: (*S)-3-(3-1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*S)-3-((3-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate. The title compound (230 mg, 59%) was prepared using analogous conditions as described in Example 126 where 7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 127) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3 [1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. MS (ESI): mass calcd. for C₄₁H₅₁F₃N₆O₆S, 812.4; m/z found, 813.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J=8.5 Hz, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.14 (d, J=7.3 Hz, 1H), 7.05-6.97 (m, 3H), 6.61 (d, J=8.4 Hz, 1H), 4.64 (s, 1H), 4.44 (s, 2H), 4.20 (s, 2H), 3.49-3.30 (m, 2H), 2.79 (d, J=16.2 Hz, 2H), 2.67-2.62 (m, 3H), 2.50-2.40 (m, 3H), 2.24 (s, 3H), 1.75-1.53 (m, 4H), 1.42 (s, 2H), 1.29 (s, 4H), 1.20 (s, 4H), 1.15 (s, 8H), 1.13-1.06 (m, 2H), 0.51-0.41 (m, 2H).

Step B: (*S)-3-(3-1′,1′-Dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoic acid. The title compound (154 mg, 72%) was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-3-((3-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₆S, 756; m/z found, 757.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (d, J=7.1 Hz, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.70 (s, 1H), 4.27 (t, J=5.9 Hz, 2H), 4.18-4.02 (m, 2H), 3.50-3.10 (m, 3H), 2.62-2.50 (m, 5H), 2.40-2.30 (m, 4H), 2.17 (s, 3H), 1.45-1.35 (m, 4H), 1.34-1.26 (m, 2H), 1.21 (s, 3H), 1.15 (s, 3H), 0.94-0.83 (m, 2H), 0.54-0.42 (m, 2H).

Example 372: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4, (3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The title compound (244 mg, 56%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 136) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide Intermediate 72) and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₂H₅₃F₃N₆O₆S, 826.4; m/z found, 827.3 [M+H]⁺.

Step B: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (190 mg, 84%) was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-[pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₄H₄₅F₃N₆O₆S, 770.3; m/z found, 771.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (d, J=1.0 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.13 (dd, J=7.9, 1.9 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 4.70 (s, 1H), 4.30 (t, J=6.0 Hz, 2H), 4.16-4.01 (m, 2H), 3.50-3.10 (m, 3H), 2.63-2.51 (m, 5H), 2.42-2.34 (m, 4H), 2.18 (s, 3H), 2.09 (d, J=0.9 Hz, 3H), 1.46-1.35 (m, 4H), 1.31 (q, J=6.0 Hz, 2H), 1.22 (s, 3H), 1.15 (s, 3H), 0.92-0.83 (m, 2H), 0.51-0.35 (m, 2H).

Example 373: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The title compound (133 mg, 32%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 137) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₁H₅₁F₃N₆O₆S, 812.4; m/z found, 813.3 [M+H]⁺.

Step B: (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₆S, 756.3; m/z found, 757.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=7.2 Hz, 1H), 7.96 (s, 1H), 7.27-7.18 (m, 2H), 7.14 (d, J=7.9 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 4.77 (s, 1H), 4.43 (t, J=5.6 Hz, 2H), 4.22-4.13 (m, 2H), 3.60-3.05 (m, 3H), 2.98 (s, 2H), 2.73 (s, 3H), 2.63 (s, 3H), 2.25 (s, 3H), 2.23-2.14 (m, 3H), 1.80-1.70 (m, 4H), 1.29 (s, 3H), 1.23 (s, 3H), 0.94 (s, 2H), 0.60-0.44 (m, 2H).

Example 374: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: tert-Butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. The title compound (183 mg, 58%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 136) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) and tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 129) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₂H₅₄F₂N₆O₆S, 808.4; m/z found, 809.3 [M+H]⁺.

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. The title compound (97 mg, 57%) was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₄H₄₆F₂N₆O₆S, 752.3; m/z found, 753.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=7.3 Hz, 1H), 7.94 (d, J=1.0 Hz, 1H), 7.76-7.58 (m, 1H), 7.24-7.18 (m, 2H), 7.16-7.07 (m, 2H), 4.75 (s, 1H), 4.37 (t, J=5.9 Hz, 2H), 4.25-4.09 (m, 2H), 3.55-3.25 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.60 (s, 3H), 2.49-2.38 (m, 4H), 2.25 (s, 3H), 2.16 (s, 3H), 1.48 (p, J=5.5 Hz, 4H), 1.38 (q, J=5.8 Hz, 2H), 1.28 (s, 3H), 1.22 (s, 3H), 1.01-0.89 (m, 2H), 0.58-0.44 (m, 2H).

Example 375: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: tert-Butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. The title compound (57 mg, 18%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 137) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide Intermediate 72) and tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 129) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₁H₅₂F₂N₆O₆S, 794.4; m/z found, 795.3 [M+H]⁺.

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. The title compound (29 mg, 55%) was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₇H₄₄F₂N₆O₆S, 738.3; m/z found, 739.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=7.3 Hz, 1H), 7.91 (s, 1H), 7.65 (t, J=51.6 Hz, 1H), 7.18-7.00 (m, 4H), 4.68 (s, 1H), 4.44 (br s, 2H), 4.10 (q, J=14.6 Hz, 2H), 3.50-3.15 (m, 9H), 2.53 (s, 3H), 2.18-2.13 (m, 6H), 1.79 (br s, 3H), 1.22 (s, 3H), 1.16 (s, 3H), 0.92-0.83 (m, 2H), 0.52-0.39 (m, 2H).

Example 376: 3-(*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-piperidin-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (65 mg, 57%) was prepared using analogous conditions as described in Example 114 where 1-(piperidin-1-yl)propan-2-amine was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 142) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₄₁H₅₂F₃N₇O₈S, 827.4; m/z found, 828.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=7.2 Hz, 1H), 7.41 (s, 1H), 7.23-7.10 (m, 3H), 7.05 (d, J=8.0 Hz, 1H), 6.25 (d, J=7.3 Hz, 1H), 4.72 (s, 1H), 4.30 (d, J=15.1 Hz, 1H), 4.25-4.09 (m, 2H), 3.78-3.65 (m, 2H), 3.41-3.10 (m, 3H), 2.57 (s, 3H), 2.40-2.32 (m, 3H), 2.30-2.22 (m, 2H), 2.20-2.09 (m, 4H), 1.93 (s, 3H), 1.44-1.35 (m, 6H), 1.35-1.08 (m, 14H).

Example 377: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: tert-Butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. The title compound (70 mg, 23%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide Intermediate 72) and tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 129) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₃H₅₆F₂N₆O₇S, 838.4; m/z found, 839.3 [M+H]⁺.

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. The title compound (35 mg, 54%) was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₉H₄₈F₂N₆O₇S, 782.3; m/z found, 783.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.62 (t, J=51.7 Hz, 1H), 7.20-7.12 (m, 3H), 7.06 (d, J=8.1 Hz, 1H), 4.71 (s, 1H), 4.43-4.22 (m, 4H), 3.76-3.65 (m, 2H), 3.48-3.15 (s, 5H), 2.87 (br s, 1H), 2.70-2.55 (m, 6H), 2.15-2.06 (m, 6H), 1.66 (br s, 4H), 1.50-1.27 (m, 4H), 1.27-1.15 (m, 7H).

Example 378: (*S)-3-(3-((7′-((2-(4-Methoxypiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: tert-Butyl (*S)-3-(3-((7′-((2-(4-methoxypiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The title compound (159 mg, 45%) was prepared using analogous conditions as described in Example 126 where 7′-((2-(4-methoxypiperidine-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 138) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide Intermediate 72) and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₃H₅₅F₃N₆O₇S, 856.4; m/z found, 857.3 [M+H]⁺.

Step B: (*S)-3-(3-((7′-((2-(4-Methoxypiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (105 mg, 72%) was prepared using analogous conditions as described in Example 370 where tert-butyl (*S)-3-(3-((7′-((2-(4-methoxypiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₃₉H₄₇F₃N₆O₇S, 800.3; m/z found, 801.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=6.9 Hz, 1H), 7.94 (s, 1H), 7.30-7.03 (m, 4H), 4.77 (s, 1H), 4.40-4.33 (m, 2H), 4.25-4.07 (m, 2H), 3.60-3.12 (m, 4H), 2.83-2.56 (m, 8H), 2.28-2.13 (m, 9H), 1.81 (d, J=12.1 Hz, 2H), 1.45-1.35 (m, 2H), 1.34-1.19 (m, 6H), 1.00-0.88 (m, 2H), 0.59-0.42 (m, 2H).

Example 379: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. The title compound (211 mg, 46%) was prepared using analogous conditions as described in Example 126 where tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 129) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. mass calcd. for C₄₄H₅₈F₂N₆O₇S, 852.4; m/z found, 853.3 [M+H]⁺.

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. The title compound (142 mg, 76%) was prepared using analogous conditions as described in Example 370 where (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₄₀H₅₀F₂N₆O₇S, 796.3; m/z found, 797.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 7.70 (t, J=51.7 Hz, 1H), 7.28-7.20 (m, 3H), 7.14 (d, J=7.7 Hz, 1H), 4.78 (s, 1H), 4.48-4.30 (m, 4H), 3.85-3.70 (m, 2H), 3.55-3.24 (m, 4H), 2.68 (t, J=6.0 Hz, 2H), 2.63 (s, 3H), 2.49-2.43 (m, 4H), 2.19 (s, 3H), 2.15 (s, 3H), 1.57-1.33 (m, 10H), 1.31 (s, 3H), 1.26 (s, 3H).

Example 380: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (125 mg, 55%) was prepared using analogous conditions as described in Example 114 where (S)-1-(piperidin-1-yl)propan-2-amine was used instead of 3-aminopropan-1-ol in Step A and methyl (*R)-3-(3((7′-chloro-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]]pyridine-7-yl)propanoate (Intermediate 143) instead of methyl 3-(3-((7′-chloro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 69). MS (ESI): mass calcd. for C₃₉H₄₈F₃N₇O₅S, 783.3; m/z found, 784.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.55 (s, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20 (dd, J=7.8, 1.9 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.04 (s, 1H), 6.40 (d, J=7.4 Hz, 1H), 4.76 (s, 1H), 4.22-3.98 (m, 3H), 3.50-3.15 (m, 2H), 2.61 (s, 3H), 2.46-2.29 (m, 5H), 2.28-2.22 (m, 4H), 2.06 (s, 3H), 1.51-1.43 (m, 4H), 1.42-1.35 (m, 2H), 1.30-1.12 (m, 9H), 0.95-0.80 (m, 2H), 0.48-0.42 (m, 1H), 0.37-0.30 (m, 1H).

Example 381: (*S)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Methyl (*S)-3-(3-(((*S)-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A mixture containing methyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 160, 100 mg, 0.220 mmol), (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 154, 63 mg, 0.25 mmol) potassium carbonate (153 mg, 1.11 mmol), and acetonitrile (2 mL) was stirred at 80° C. After 16 hours, the mixture was cooled to room temperature and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil (180 mg). This material was used without further purification. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₆S, 673.2; m/z found, 674.1 [M+H]⁺.

Step B: (*S)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Sodium hydroxide (42 mg, 1.1 mmol) was added to a stirring solution of methyl (*S)-3-(3-(((*S)-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (140 mg, 0.208) in dioxane-water (1:1, 3 mL). The mixture was warmed to 65° C. After 6 hours, the reaction was cooled to room temperature. 1 M aqueous HCl solution was added until the pH was 5 and then the mixture was extracted with ethyl acetate. This resulted in numerous organic fractions which were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol) and then by reverse phase HPLC (Agela Durashell C18, 150×25 mm×5 μm column, eluent: 38% to 68% (v/v) CH₃CN in H₂O with 0.225% formic acid) to provide the title compound (20 mg, 15%). MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (br s, 1H), 8.55 (dd, J=2.0, 4.9 Hz, 1H), 8.41 (d, J=7.3 Hz, 1H), 8.20 (dd, J=1.8, 7.7 Hz, 1H), 7.48 (dd, J=4.9, 7.6 Hz, 1H), 7.27-7.21 (m, 2H), 7.20-7.18 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 4.79 (s, 1H), 4.36-4.20 (m, 2H), 3.97-3.89 (m, 1H), 3.83-3.75 (m, 1H), 3.72-3.67 (m, 1H), 3.59-3.49 (m, 2H), 3.38-3.37 (m, 1H), 2.64 (s, 3H), 2.20 (s, 3H), 1.90-1.82 (m, 1H), 1.77-1.68 (m, 1H), 1.30 (s, 3H), 1.24 (s, 3H).

Example 382: (*S)-3-(3-(((*R)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (67 mg) was prepared using analogous conditions as described in Example 381 using (*R)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 155) instead of (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.55 (br s, 1H), 8.55 (dd, J=1.9, 4.9 Hz, 1H), 8.42 (d, J=7.3 Hz, 1H), 8.20 (dd, J=2.0, 7.5 Hz, 1H), 7.48 (dd, J=4.8, 7.5 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.24 (s, 1H), 7.21-7.17 (m, 1H), 7.15-7.11 (m, 1H), 4.79 (s, 1H), 4.37-4.22 (m, 2H), 4.01-3.94 (m, 1H), 3.85-3.79 (m, 1H), 3.76-3.61 (m, 3H), 3.44-3.41 (m, 1H), 2.64 (s, 3H), 2.19 (s, 3H), 1.91-1.78 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H).

Example 383: (*S)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (57 mg) was prepared using analogous conditions as described in Example 381 using (*S)-8′-methyl-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 156) instead of (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₆S, 673.2; m/z found, 674.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (br s, 1H), 8.41 (d, J=7.1 Hz, 1H), 8.37-8.35 (m, 1H), 8.04-7.99 (m, 1H), 7.27-7.21 (m, 2H), 7.19-7.17 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.79 (s, 1H), 4.36-4.19 (m, 2H), 3.96-3.87 (m, 1H), 3.80-3.65 (m, 2H), 3.58-3.45 (m, 2H), 3.36-3.35 (m, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H), 1.90-1.81 (m, 1H), 1.76-1.65 (m, 1H), 1.31 (s, 3H), 1.25 (s, 3H).

Example 384: (*S)-2,2-Dimethyl-3-(4-methyl-3-(((*R)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (97 mg) was prepared using analogous conditions as described in Example 381 using (*R)-8′-methyl-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 157) instead of (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₆S, 673.2; m/z found, 674.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.54 (br s, 1H), 8.42 (d, J=7.3 Hz, 1H), 8.39-8.35 (m, 1H), 8.04-8.00 (m, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.24 (s, 1H), 7.21-7.17 (m, 1H), 7.15-7.11 (m, 1H), 4.79 (s, 1H), 4.35-4.22 (m, 2H), 4.01-3.93 (m, 1H), 3.83-3.57 (m, 4H), 3.42-3.39 (m, 1H), 2.64 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H), 1.92-1.77 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H).

Example 385: (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (42 mg) was prepared using analogous conditions as described in Example 381 using methyl (*R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 161 instead of methyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate in Step A. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (br s, 1H), 8.56-8.53 (m, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.22-8.18 (m, 1H), 7.50-7.45 (m, 1H), 7.28-7.21 (m, 2H), 7.19 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 4.79 (s, 1H), 4.37-4.20 (m, 2H), 3.97-3.88 (m, 1H), 3.79 (d, J=15.6 Hz, 1H), 3.69 (d, J=10.0 Hz, 1H), 3.60-3.48 (m, 2H), 3.38 (s, 1H), 2.64 (s, 3H), 2.20 (s, 3H), 1.90-1.82 (m, 1H), 1.79-1.66 (m, 1H), 1.30 (s, 3H), 1.25 (s, 3H).

Example 386: (*R)-3-(3-(((*R)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (41 mg) was prepared using analogous conditions as described in Example 381 using methyl (*R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 161) instead of methyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and (*R)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 155) instead of (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (br s, 1H), 8.56-8.53 (m, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.22-8.18 (m, 1H), 7.50-7.45 (m, 1H), 7.28-7.21 (m, 2H), 7.19 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 4.79 (s, 1H), 4.37-4.20 (m, 2H), 3.97-3.88 (m, 1H), 3.79 (d, J=15.6 Hz, 1H), 3.69 (d, J=10.0 Hz, 1H), 3.60-3.48 (m, 2H), 3.38 (s, 1H), 2.64 (s, 3H), 2.20 (s, 3H), 1.90-1.82 (m, 1H), 1.79-1.66 (m, 1H), 1.30 (s, 3H), 1.25 (s, 3H).

Example 387: (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (76 mg) was prepared using analogous conditions as described in Example 381 using methyl (*R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 161) instead of methyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and (*S)-8′-methyl-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 156) instead of (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₆S, 673.2; m/z found, 674.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (br s, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.23 (s, 1H), 7.21-7.17 (m, 1H), 7.15-7.11 (m, 1H), 4.79 (s, 1H), 4.35-4.21 (m, 2H), 4.01-3.93 (m, 1H), 3.79 (d, J=15.4 Hz, 1H), 3.75-3.71 (m, 1H), 3.69 (d, J=10.4 Hz, 1H), 3.61 (br d, J=15.4 Hz, 1H), 3.41 (d, J=10.0 Hz, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.92-1.76 (m, 2H), 1.31 (s, 3H), 1.25 (s, 3H).

Example 388: (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*R)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (18 mg) was prepared using analogous conditions as described in Example 381 using methyl (*R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 161) instead of methyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate and (*R)-8′-methyl-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 157) instead of (*S)-2′,3′,4,5-tetrahydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₆S, 673.2; m/z found, 674.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=1.6 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.19-7.11 (m, 3H), 4.80 (s, 1H), 4.49-4.36 (m, 2H), 4.14-4.03 (m, 2H), 3.87 (d, J=10.4 Hz, 1H), 3.77-3.61 (m, 2H), 3.55 (d, J=10.4 Hz, 1H), 2.83 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H), 2.10-2.06 (m, 1H), 1.84-1.75 (m, 1H), 1.41 (s, 3H), 1.35 (s, 3H).

Example 389: (*S)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d[1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 264, 86 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 60% CO₂, 40% iPrOH) to afford two isomers. The first eluting isomer (41 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄S, 614.2; m/z found, 615.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=7.2 Hz, 1H), 8.35-8.31 (m, 1H), 8.02-7.97 (m, 1H), 7.26-7.20 (m, 1H), 7.20-7.16 (m, 1H), 7.16-7.08 (m, 2H), 6.93-6.88 (m, 1H), 4.86-4.79 (m, 1H), 4.40-4.23 (m, 2H), 4.16-4.10 (m, 1H), 3.62-3.45 (m, 2H), 3.15-3.07 (m, 1H), 2.97-2.86 (m, 3H), 2.74 (s, 3H), 2.21 (s, 3H), 2.00-1.87 (m, 1H), 1.71-1.51 (m, 2H), 1.46-1.35 (m, 1H).

Example 390: (*R)-3-(3-(((R)-5,5-Dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (38 mg) from the chiral separation described in Example 389 was designated (*R). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₄S, 614.2; m/z found, 615.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.3 Hz, 1H), 8.36-8.31 (m, 1H), 8.03-7.98 (m, 1H), 7.26-7.21 (m, 1H), 7.18-7.10 (m, 3H), 6.95-6.89 (m, 1H), 4.80 (t, J=7.7 Hz, 1H), 4.30-4.15 (m, 3H), 3.68-3.57 (m, 1H), 3.51-3.42 (m, 1H), 3.08-2.90 (m, 4H), 2.70 (s, 3H), 2.22 (s, 3H), 1.92-1.78 (m, 1H), 1.75-1.57 (m, 2H), 1.45-1.35 (m, 1H).

Example 391: (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: (R/S)-Methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A solution of methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 55, 201.7 mg, 0.495 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 131.8 mg, 0.549 mmol), and triphenylphosphine (210 mg, 0.801 mmol) in THF (7.5 mL) was stirred at room temperature for 1 minute. DBAD (183 mg, 0.795 mmol) was added and the solution was stirred at room temperature for 5 hours. The reaction was then concentrated and purified by flash column chromatography (10% EtOAc/hexanes 10% MeOH/DCM) to afford the title compound (212.9 mg, 68% yield). MS (ESI): mass calcd. for C₃₄H₃₉N₅O₅S, 629.3; m/z found, 630.3 [M+H]⁺.

Step B: (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Aqueous lithium hydroxide (2M, 5 mL, 10 mmol) was added to a solution of (R/S)-methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3 yl)methyl)phenyl)propanoate (300 mg, 0.105 mmol) in MeOH (10 mL). The reaction was stirred at 70° C. overnight, then allowed to cool to room temperature. The reaction was acidified to pH 3-4 using 1M HCl and then extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by FCC (0-50% MeOH/EtOAc) and repurified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA). The pure fractions resulting from the preparative acidic HPLC were collected and lyophilized to dryness to provide the title compound (125.1 mg, 43% yield). MS (ESI): mass calcd. for C₃₃H₃₇N₅O₅S, 615.2; m/z found, 616.3 [M+H]⁺.

Example 392: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 391) was separated by chiral SFC (Chiralpak AS-H, mobile phase: 80% CO₂, 20% MeOH) to afford two enantiomers. The first eluting isomer (59 mg) was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₇N₅O₅S, 615.2; m/z found, 616.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28-8.21 (m, 1H), 8.08 (s, 1H), 7.99-7.89 (m, 1H), 7.19-7.06 (m, 4H), 4.76 (s, 1H), 4.34-4.20 (m, 2H), 3.55-3.40 (m, 2H), 2.63 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 1.99 (s, 1H), 1.45-1.30 (m, 6H), 1.22-0.92 (m, 6H), 0.57-0.39 (m, 2H).

Example 393: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (45 mg) from the chiral separation described in Example 392 was designated (*R): MS (ESI): mass calcd. for C₃₃H₃₇N₅O₅S, 615.2; m/z found, 616.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.24 (s, 1H), 8.10-8.05 (m, 1H), 7.94-7.88 (m, 1H), 7.18 -7.06 (m, 4H), 4.76 (s, 1H), 4.37-4.21 (m, 2H), 3.48 (s, 2H), 2.61 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H), 1.98 (s, 1H), 1.47-1.29 (m, 6H), 1.22-0.92 (m, 6H), 0.55-0.37 (m, 2H).

Example 394: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The title compound (200 mg, 55% yield) was prepared using analogous conditions as described in Example 391 where methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoate (Intermediate 56) was used instead of methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.2; m/z found, 617.3 [M+H]⁺.

Example 395: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-54(8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The mixture of (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-54(8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid isomers (Example 394) was separated by chiral SFC (Chiralpak AS-H, mobile phase: 80% CO₂, 20% MeOH) to afford two enantiomers. The first eluting isomer (75 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.2; m/z found, 617.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.59-8.54 (m, 1H), 8.25-8.21 (m, 1H), 8.05-8.01 (m, 1H), 7.61-7.56 (m, 1H), 7.52 (s, 1H), 7.51-7.47 (m, 1H), 5.05 (s, 1H), 4.36-4.13 (m, 2H), 3.79-3.71 (m, 1H), 3.57-3.29 (m, 2H), 2.86 (s, 3H), 2.54 (s, 3H), 2.39 (s, 3H), 1.46-1.07 (m, 12H), 0.49-0.32 (m, 2H).

Example 396: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-54(8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The second eluting isomer (61 mg) from the chiral separation described in Example 395 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.2; m/z found, 617.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.56-8.54 (m, 1H), 8.25-8.22 (m, 1H), 8.04-8.01 (m, 1H), 7.60-7.57 (m, 1H), 7.51-7.44 (m, 2H), 5.06 (s, 1H), 4.37-4.11 (m, 2H), 3.79-3.72 (m, 1H), 3.58-3.27 (m, 2H), 2.87 (s, 3H), 2.53 (s, 3H), 2.43-2.35 (m, 3H), 1.50-1.23 (m, 12H), 0.48-0.28 (m, 2H).

Example 397: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The title compound (480 mg, 93% yield) was prepared using analogous conditions as described in Example 391 where ethyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Intermediate 32 Step B) was used instead of methyl 3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate and (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2) was used instead of 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 616.2; m/z found, 601.3 [M+H]⁺.

Example 398: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 397) was separated by chiral SFC (1′ separation: Chiralpak IA, mobile phase: 50% CO₂, 50% EtOH, 2^(nd) separation: Chiralpak OD-H, mobile phase: 70% CO₂, 30% MeOH) to afford two diastereomers. The first eluting isomer (188 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.2; m/z found, 601.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.30-8.25 (m, 1H), 8.03 (dd, J=7.8, 1.9 Hz, 1H), 7.46-7.42 (m, 1H), 7.37-7.32 (m, 1H), 7.11-7.04 (m, 3H), 6.81 (dd, J=7.8, 4.7 Hz, 1H), 4.98-4.91 (m, 1H), 4.50-4.45 (m, 1H), 4.42 (d, J=14.3 Hz, 1H), 4.22-4.09 (m, 2H), 3.75-3.68 (m, 1H), 3.21-3.01 (m, 5H), 2.80 (s, 3H), 2.24 (s, 3H), 1.64-1.55 (m, 1H), 1.51-1.21 (m, 9H).

Example 399: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (191 mg) from the chiral separation described in Example 398 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.2; m/z found, 601.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29-8.25 (m, 1H), 8.04 (dd, J=7.8, 1.9 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.13-7.09 (m, 2H), 7.07 (s, 1H), 6.81 (dd, J=7.8, 4.7 Hz, 1H), 4.99-4.91 (m, 1H), 4.50-4.40 (m, 2H), 4.22-4.14 (m, 1H), 4.14-4.08 (m, 1H), 3.74-3.68 (m, 1H), 3.18-3.00 (m, 5H), 2.83 (s, 3H), 2.25 (s, 3H), 1.69-1.46 (m, 3H), 1.40-1.14 (m, 7H).

Example 400: 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetate salt

Step A: Ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate. A solution of ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 11, Step A, 218 mg, 0.535 mmol) in DCM (2.1 mL) was treated with thionyl chloride (0.16 mL, 2.2 mmol) in one portion under air at room temperature, and the vial was sealed and stirred for a few minutes. The reaction was then treated with DMF (30 μL, 0.39 mmol) and stirred at room temperature under air (sealed) for 55 minutes. The solution was then treated with 6 mL 1 M NaHCO₃ and 4 mL DCM and stirred for 10 minutes. The aqueous layer was extracted with DCM (4 mL), the organic layers combined, dried (Na₂SO₄), filtered, and concentrated to provide the title compound as a clear yellow oil (211 mg, 92%) which was used in the next step without further purification. MS (ESI): mass calcd. for C₂₄H₂₈ClN₃O₂, 425.2; m/z found, 426.1 [M+H]⁺.

Step B: Ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate. A vial was charged with 3 Å molecular sieves (1 bead; freshly activated under vacuum with heat gun for 2 min), (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 63.9 mg, 0.267 mmol), and DMF (0.6 mL). The solution was stirred under positive argon pressure (capped) for 10 minutes, and was then treated with sodium hydride (60.8% dispersion in mineral oil) (13.8 mg, 0.35 mmol) in one portion at room temperature under air. The reaction was immediately sealed and stirred on an ice bath under positive argon pressure for 10 minutes, and was then treated with a solution of ethyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate in DMF (0.53 mL, 0.46 M, 0.244 mmol) dropwise over 2 minutes. The reaction mixture was stirred on an ice bath for 1.5 hours, then removed from the ice bath and stirred at room-temperature for 40 minutes. The reaction was quenched with 3 mL 1 M NaH₂PO₄ and extracted with EtOAc (2×3 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give the title compound as a clear yellow oil (146 mg) that was used in the next step without further purification. MS (ESI): mass calcd. for C₃₄H₄₀N₆O₄S, 628.3; m/z found, 629.4 [M+H]⁺.

Step C: 3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid trifluoroacetate. A vial containing ethyl 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (146 mg, 0.233 mmol) was charged with THF (1 mL), MeOH (1 mL), and NaOH (3M in H₂O) (0.25 mL, 0.75 mmol), and the resulting mixture was stirred at room temperature under air (capped) for 30 minutes, then for 30 minutes at 60° C. The reaction was concentrated and the residue partitioned with 0.75 mL 1 M HCl, 1 mL 1 M NaH₂PO₄, and 5 mL EtOAc. The aqueous layer was extracted with EtOAc (1×2 mL), and the combined organic layers were dried (Na₂SO₄), filtered, and concentrated to provide 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. The compound was purified by C18 reverse phase HPLC (10-90% CH₃CN—H₂O, 0.1% TFA) to provide 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid as its trifluoroacetate salt (145 mg). MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25-8.17 (m, 2H), 7.62-7.56 (m, 1H), 7.52-7.40 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.17-7.13 (m, 1H), 7.09-7.04 (m, 1H), 6.97-6.92 (m, 1H), 5.00-4.94 (m, 1H), 4.61-4.52 (m, 3H), 4.45-4.37 (m, 1H), 4.18-4.11 (m, 1H), 3.60-3.42 (m, 2H), 3.20-3.01 (m, 3H), 2.94-2.76 (m, 4H), 2.25 (s, 3H), 1.98-1.86 (m, 1H), 1.78-1.67 (m, 1H), 1.63-1.50 (m, 1H), 1.48-1.31 (m, 2H), 0.65-0.47 (m, 4H).

Example 401: (*R)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The isomeric mixture of 3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid as the trifluoroacetate salts (Example 400, 140 mg) were separated by chiral SFC (stationary phase: Chiralpak IA, 250×20 mm, mobile phase: 65% CO₂, 35% EtOH) to afford two diastereoisomers. The first eluting isomer (44 mg, 31%) was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ (dd, J=1.8, 4.8 Hz, 1H), 8.08 (dd, J=1.8, 7.8 Hz, 1H), 7.36-7.29 (m, 2H), 7.09 (d, J=1.5 Hz, 3H), 6.83-6.79 (m, 1H), 4.96 (t, J=7.8 Hz, 1H), 4.59-4.51 (m, 1H), 4.49-4.39 (m, 3H), 4.12 (d, J=13.6 Hz, 1H), 3.73 (q, J=6.7 Hz, 1H), 3.64-3.57 (m, 2H), 3.22-3.03 (m, 3H), 2.85 (s, 3H), 2.82-2.76 (m, 1H), 2.27 (s, 3H), 1.97-1.86 (m, 1H), 1.85-1.70 (m, 1H), 1.46-1.34 (m, 2H), 0.63 (td, J=5.6, 8.1 Hz, 2H), 0.50-0.45 (m, 2H).

Example 402: (*S)-3-(1-(Cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6 (7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (41 mg, 29%) from the chiral separation described in Example 401 was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₄S, 600.3; m/z found, 601.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ (dd, J=1.8, 4.8 Hz, 1H), 8.04 (dd, J=2.0, 7.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.23 (dd, J=1.5, 7.6 Hz, 1H), 7.17-7.12 (m, 1H), 7.02 (s, 1H), 6.88-6.84 (m, 1H), 4.99-4.93 (m, 1H), 4.55 (d, J=7.1 Hz, 2H), 4.43-4.29 (m, 2H), 4.14 (d, J=13.6 Hz, 1H), 3.56 (dt, J=5.8, 10.7 Hz, 1H), 3.40-3.33 (m, 1H), 3.16-3.01 (m, 3H), 2.93-2.80 (m, 1H), 2.76 (s, 3H), 2.26 (s, 3H), 1.94-1.82 (m, 1H), 1.72-1.57 (m, 2H), 1.51-1.33 (m, 2H), 0.67-0.47 (m, 4H)

Example 403: 3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid and its trifluoroacetate salt

Step A: Methyl 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate. A vial was charged with (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 57.5 mg, 0.227 mmol) and DMF (0.52 mL). The solution was then treated with sodium hydride (60.8% dispersion in mineral oil) (11.1 mg, 0.281 mmol) in one portion at room temperature under air. The reaction was immediately sealed and stirred on an ice bath under positive argon pressure for 10 minutes, and was then treated with a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoate in DMF (0.448 mL, 0.46 M, 0.206 mmol) dropwise over 2 minutes. The reaction mixture was stirred on an ice bath for 20 minutes. The reaction was quenched with 3 mL 1 M NaH₂PO₄ and extracted with EtOAc (2×3 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give the title compound as a clear yellow oil (142 mg) that was used in the next step without further purification. MS (ESI): mass calcd. for C₃₃H₃₈N₆O₅S, 630.3; m/z found, 631.3 [M+H]⁺.

Step B: 3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid trifluoroacetate. Methyl 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate (130 mg, 0.206 mmol) was treated with LiOH (1M in H₂O) (0.62 mL, 0.62 mmol), MeOH (0.82 mL), and THF (0.82 mL). The resulting mixture was stirred under air (capped) at 60° C. for 40 min, and was then cooled to room temperature and brought to pH 2 with 4.3 eq TFA (68 uL), brought to 3 mL volume with MeOH, and filtered through a 0.45 μm syringe filter to afford 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. This compound was purified by C18 reverse phase HPLC (10-90% CH₃CN—H₂O, 0.1% TFA) to provide 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid as its trifluoroacetate salt(84 mg, 56%). MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.2; m/z found, 617.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J=4.8 Hz, 1H), 8.15-8.11 (m, 1H), 7.43 (d, J=10.1 Hz, 1H), 7.29 (dt, J=1.5, 8.1 Hz, 1H), 7.21-7.12 (m, 3H), 6.96 (ddd, J=1.5, 4.9, 7.7 Hz, 1H), 4.66-4.59 (m, 1H), 4.45-4.38 (m, 2H), 4.37-4.35 (m, 3H), 4.31-4.19 (m, 1H), 4.01-3.92 (m, 2H), 3.28-3.21 (m, 1H), 3.15-2.98 (m, 4H), 2.22 (d, J=4.0 Hz, 3H), 1.68-1.49 (m, 2H), 1.44-1.28 (m, 3H), 1.28-1.11 (m, 1H), 0.92-0.73 (m, 4H).

Example 404: (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(7-cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid trifluoroacetate isomers (Example 403, 79 mg) were separated by chiral SFC (stationary phase: Chiralpak AD-H, 250×30 mm, mobile phase: 70% CO₂, 30% EtOH) to afford two diastereoisomers. The first eluting isomer (28 mg, 35%) was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.2; m/z found, 617.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (dd, J=1.8, 4.8 Hz, 1H), 8.00 (dd, J=1.8, 7.8 Hz, 1H), 7.45 (s, 1H), 7.30 (dd, J=1.8, 7.8 Hz, 1H), 7.19-7.13 (m, 3H), 6.87 (dd, J=4.8, 7.8 Hz, 1H), 4.64 (t, J=8.1 Hz, 1H), 4.42-4.30 (m, 5H), 4.29-4.18 (m, 1H), 4.06 (td, J=4.7, 13.3 Hz, 1H), 3.96 (tt, J=3.0, 6.1 Hz, 1H), 3.25-3.05 (m, 4H), 2.96 (ddd, J=3.5, 10.2, 13.5 Hz, 1H), 2.22 (s, 3H), 1.65-1.50 (m, 2H), 1.40-1.28 (m, 3H), 1.20-1.07 (m, 1H), 0.93-0.72 (m, 4H).

Example 405: (*S)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (31 mg, 39%) from the chiral separation described in Example 404 was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₆N₆O₅S, 616.2; m/z found, 617.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (dd, J=1.8, 4.8 Hz, 1H), 8.01 (dd, J=1.8, 7.8 Hz, 1H), 7.42 (s, 1H), 7.27 (dd, J=1.8, 7.8 Hz, 1H), 7.22-7.13 (m, 3H), 6.87 (dd, J=4.5, 7.6 Hz, 1H), 4.63 (br t, J=7.8 Hz, 1H), 4.43-4.27 (m, 5H), 4.27-4.20 (m, 1H), 4.10-3.93 (m, 2H), 3.24 (dd, J=12.4, 13.4 Hz, 1H), 3.16-2.99 (m, 4H), 2.22 (s, 3H), 1.66-1.40 (m, 3H), 1.32-1.25 (m, 3H), 0.93-0.73 (m, 4H).

Example 406: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol. A solution of nBuLi (2.95 mL, 2.5 M in Hexanes, 7.38 mmol) was added dropwise at −78° C. to ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 1.78 g, 5.67 mmol) in THF (80 mL). The resulting mixture was stirred for 1 hour. 8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde (Intermediate 28, 1.30 g, 5.67 mmol) in THF (5 mL) was then added dropwise. The resulting solution was warmed to room temperature over a period of 4 hours and quenched with a saturated aqueous NH₄Cl solution (40 mL). The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc/Hexanes) to provide the title compound (1.60 g, 60.6%). MS (ESI): mass calcd. for C₂₃H₃₀F₃N₃O₂Si, 465.21; m/z found, 466.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=7.2 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.36-7.31 (m, 1H), 7.18 (dd, J=7.7, 2.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.13 (d, J=3.2 Hz, 1H), 4.61 (s, 2H), 2.65-2.61 (m, 4H), 2.18 (s, 3H), 0.82 (s, 9H), 0.01 (d, J=8.5 Hz, 6H).

Step B: Methyl 3-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 2,2,2-Trichloroacetonitrile (1.29 g, 8.94 mmol) and DBU (80.0 mg, 0.525 mmol) were added to (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (1.60 g, 3.44 mmol) in acetonitrile (5 mL) at room temperature, and the mixture was stirred for 45 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.38 g, 7.90 mmol) and bis(trifluoromethanesulfonyl)imide (96.6 mg, 0.344 mmol) were then added sequentially, and the mixture was stirred at room temperature for 16 hours. Another portion of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.38 g, 7.90 mmol) and bis(trifluoromethanesulfonyl)imide (96.6 mg, 0.344 mmol) were then added sequentially, and the mixture was stirred at 50° C. for 16 hours. The reaction was quenched with aqueous saturated NaHCO₃ solution (20 mL) and extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc/Hexanes) to provide the title compound (1.20 g, 63%). MS (ESI): mass calcd. for C₂₈H₃₈F₃N₃O₃Si, 549.26; m/z found, 550.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J=7.3 Hz, 1H), 7.27-7.14 (m, 2H), 7.01 (d, J=1.3 Hz, 2H), 4.79 (s, 1H), 4.60 (s, 2H), 3.55 (s, 3H), 2.73 (s, 3H), 2.16 (s, 3H), 1.39 (s, 3H), 1.32 (s, 3H), 0.83 (s, 9H), 0.00 (d, J=3.6 Hz, 6H).

Step C: Methyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Methyl 3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (550 mg, 1.00 mmol) was dissolved in DCM (10 mL), and SOCl₂ (0.31 mL, 4.33 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified with flash column chromatography (10% EtOAc/Hexanes) to provide the title compound (400 mg, 88%). MS (ESI): mass calcd. for C₂₂H₂₃ClF₃N₃O₂, 453.14; m/z found, 454.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.95 (d, J=7.3 Hz, 1H), 7.20-7.02 (m, 4H), 4.79 (s, 1H), 4.62-4.47 (m, 2H), 3.55 (s, 3H), 2.79 (s, 3H), 2.39 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H).

Step D: 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. DMF (0.5 mL) was added to a stirring mixture of 8′-methyl-2,2′,3,3′,5,6-Hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 200 mg, 0.703 mmol) and KOtBu (118 mg, 1.05 mmol). After 10 minutes, a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (319 mg, 0.703 mmol) in DMF (0.5 mL) was added and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated under reduced pressure. LiOH (3M, 1 mL) was added to the residue in THF (1 mL) and MeOH (1 mL), The mixture was heated at 50° C. for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (150 mg, 31%). MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.23; m/z found, 688.3 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.17-8.20 (m, 2H), 7.93 (d, J=2.3 Hz, 1H), 7.40 (d, J=7.3 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 6.96 (s, 1H), 4.83 (s, 1H), 4.50-4.22 (m, 2H), 3.77-3.64 (m, 2H), 3.33-3.24 (m, 2H), 3.20-3.02 (m, 2H), 2.55 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H), 1.44-1.33 (m, 2H), 1.26 (s, 3H), 1.16 (s, 3H), 1.12-1.02 (m, 2H).

Example 407: (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of isomers of 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 406, 150 mg) were separated by chiral SFC (stationary phase: OZ-H 2×25 cm, mobile phase: 60% CO₂, 40% MeOH) to afford two enantiomers. The first eluting enantiomer (68 mg) was designated 9*S): MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.23; m/z found, 688.3 [M+H]⁺.

Example 408: (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (53 mg) from the chiral separation described in Example 407 was designated (*R): MS (ESI): mass calcd. for C₃₃H₃₆F₃N₅O₆S, 687.23; m/z found, 688.3 [M+H]⁺.

Example 409: (*S)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (111 mg, 23.4% yield) was prepared using analogous conditions as described in Example 406 where 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36) was used instead of 8′-methyl-2,2′,3,3′,5,6-Hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step D. MS (ESI): mass calcd. for C₃₃H₃₄F₃N₅O₆S, 673.22; m/z found, 674.3 [M+H]⁺. The mixture of isomers of 3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (106 mg) was separated by chiral SFC (stationary phase: IC 2×25 cm, mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The first eluting enantiomer (44 mg) was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₄F₃N₅O₆S, 673.22; m/z found, 674.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (dd, J=4.9, 1.9 Hz, 1H), 8.20 (dd, J=7.6, 1.9 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.33-7.20 (m, 3H), 7.17-7.01 (m, 2H), 4.87 (s, 1H), 4.59-4.37 (m, 2H), 4.09-3.93 (m, 2H), 3.74-3.31 (m, 4H), 2.77 (s, 3H), 2.23 (s, 3H), 1.66-1.45 (m, 4H), 1.40-1.10 (m, 6H).

Example 410: (*R)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (42 mg) from the chiral separation described in Example 409 was designated (*R): mass calcd. for C₃₃H₃₄F₃N₅O₆S, 673.22; m/z found, 674.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) □ 8.48 (dd, J=5.0, 1.9 Hz, 1H), 8.18 (dd, J=7.5, 1.9 Hz, 1H), 7.98 (d, J=6.8 Hz, 1H), 7.37-7.15 (m, 3H), 7.04 (br s, 2H), 4.95-4.78 (m, 1H), 4.62-4.34 (m, 2H), 4.05-3.88 (m, 2H), 3.69-3.40 (m, 4H), 2.75 (s, 3H), 2.21 (s, 3H)

Example 414: (*S)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Thionyl chloride (200 mg, 1.69 mmol) was added to ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 146 mg, 0.347 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. iPr₂NEt (0.5 mL) was added to a mixture of 8′-fluoro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 166, 100 mg, 0.347 mmol), ethyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (152 mg, 0.347 mmol) in CH₃CN. The mixture was stirred at 150° C. for 16 hours. The mixture was concentrated under reduced pressure. NaOH (1M, 2 mL) was added to the residue in THF (2 mL). The mixture was stirred at RT for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (35 mg, 15%). MS (ESI): mass calcd. for C₃₀H₂₉F₄N₅O₆S, 663.18; m/z found, 664.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.26 (d, J=3.1 Hz, 1H), 8.17 (d, J=7.1 Hz, 1H), 7.90 (dd, J=6.7, 3.1 Hz, 1H), 7.27-7.18 (m, 1H), 7.13-7.06 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 4.98-4.85 (m, 1H), 4.52-4.30 (m, 2H), 3.77-3.57 (m, 2H), 3.36-3.26 (m, 2H), 3.21-3.10 (m, 2H), 3.00-2.77 (m, 2H), 2.66 (s, 3H), 2.13 (s, 3H), 1.49-1.34 (m, 2H), 1.23-1.01 (m, 2H).

Example 415: (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Thionyl chloride (200 mg, 1.69 mmol) was added to ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 519 mg, 1.23 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. iPr₂NEt (0.5 mL) was added to a mixture of 8-fluoro-2,2′,3,3′,5′,6′-hexahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran] 1,1-dioxide (Intermediate 164, 352 mg, 1.23 mmol) and ethyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (540 mg, 1.23 mmol) in CH₃CN (3 mL). The mixture was stirred at 150° C. for 16 hours. The mixture was concentrated under reduced pressure providing the title compound (650 mg, 94.1%). MS (ESI): mass calcd. for C₃₃H₃₄F₄N₄O₆S, 690.21; m/z found, 690.8 [M+H]⁺.

Step B: (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. NaOH (1M, 2 mL) was added to ethyl (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (100 mg) in THF (2 mL). The mixture was stirred at RT for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to ˜3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (63 mg, 66%). MS (ESI): mass calcd. for C₃₁H₃₀F₄N₄O₆S, 662.18; m/z found, 662.8 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.18 (d, J=7.2 Hz, 1H), 7.43-7.32 (m, 1H), 7.29-7.14 (m, 3H), 7.12-7.06 (m, 2H), 7.00 (d, J=2.2 Hz, 1H), 4.97-4.86 (m, 1H), 4.51-4.25 (m, 2H), 3.55-3.37 (m, 2H), 3.23-3.04 (m, 4H), 2.93-2.78 (m, 2H), 2.67 (s, 3H), 2.13 (s, 3H), 1.45-1.34 (m, 2H), 1.17-1.02 (m, 2H).

Example 416: (3 S*)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

LDA (0.796 mL, 1.0 M in THF, 0.796 mmol) was added dropwise at −78° C. to ethyl (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 415, Step A; 250 mg, 0.362 mmol) in THF (2 mL). The resulting mixture was stirred for 0.5 hour. Methyl iodide (0.0563 mL, 0.905 mmol) in THF (1 mL) was added. The resulting solution was warmed to room temperature over a period of 2 hours. NH₄Cl saturated solution (5 mL) was added. The aqueous layer was extracted with CH₂Cl₂ (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. NaOH (1M, 2 mL) was added to the residue in THF (2 mL). The mixture was stirred at RT for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% ethanol/CH₂Cl₂) to provide the title compound (51 mg, 21% yield). MS (ESI): mass calcd. for C₃₂H₃₂F₄N₄O₆S, 676.20; m/z found, 677.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.18 (d, J=7.2 Hz, 1H), 7.47-7.36 (m, 2H), 7.29-7.14 (m, 4H), 7.07 (d, J=7.7 Hz, 1H), 4.55-4.31 (m, 3H), 3.51-3.27 (m, 3H), 3.17-2.99 (m, 4H), 2.65 (s, 3H), 2.10 (s, 3H), 1.44-1.28 (m, 2H), 1.10-0.92 (m, 5H).

Example 417: 3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic acid

Thionyl chloride (200 mg, 1.69 mmol) was added to ethyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)propanoate (Intermediate 115, 382 mg, 1.50 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. iPr₂NEt (0.5 mL) was added to a mixture of the residue and 8-fluoro-2,2′,3,3′,5′,6′-hexahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran] 1,1-dioxide (Intermediate 164, 431 mg, 1.50 mmol) in CH₃CN (3 mL). The mixture was stirred at 150° C. for 16 hours. The mixture was concentrated under reduced pressure. NaOH (1M, 2 mL) was added to the residue in THF (2 mL). The mixture was stirred at room temperature for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (44 mg, 4.3%). MS (ESI): mass calcd. for C₃₁H₃₄FN₅O₆S, 623.22; m/z found, 624.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.61 (d, J=8.7 Hz, 1H), 7.54-7.45 (m, 3H), 7.35 (dd, J=8.7, 4.4 Hz, 1H), 7.30-7.19 (m, 2H), 5.20-5.10 (m, 1H), 4.72-4.50 (m, 4H), 3.74-3.57 (m, 2H), 3.56-3.37 (m, 4H), 3.33-3.25 (m, 1H), 3.02-2.90 (m, 1H), 2.95 (s, 3H), 2.28 (s, 3H), 1.61-1.52 (m, 3H), 1.52-1.42 (m, 2H), 1.35-1.18 (m, 2H).

Example 418: (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic acid

The mixture of 3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic acid (44 mg, Example 417) were separated by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% MeOH) to afford two enantiomers. The first eluting enantiomer (19 mg) was designated (*S): MS (ESI): mass calcd. for C₃₁H₃₄FN₅O₆S, 623.22; m/z found, 624.3 [M+H]⁺.

Example 419: (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)propanoic acid

The second eluting enantiomer (21 mg) from the chiral separation described in Example 418 was designated (*R): MS (ESI): mass calcd. for C₃₁H₃₄FN₅O₆S, 623.22; m/z found, 624.3 [M+H]⁺.

Example 420: (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid (23 mg, 10% yield) was prepared using analogous conditions as described in Example 14 where 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide(Intermediate 37) was used in Step C. MS (ESI): mass calcd. for C₃₄H₄₁N₅O₆S, 647.28; m/z found, 648.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.15 (d, J=2.3 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.26-7.20 (m, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 4.95 (s, 1H), 4.61-4.55 (m, 2H), 4.40-4.36 (m, 1H), 4.25-4.21 (m, 1H), 3.75-3.64 (m, 2H), 3.30-3.23 (m, 2H), 3.14-3.08 (m, 2H), 2.57 (s, 3H), 2.28 (s, 3H), 2.16 (s, 3H), 1.52-1.45 (m, 3H), 1.36-1.22 (m, 5H), 1.12-1.08 (s, 3H), 1.02-0.93 (m, 1H), 0.85-0.75 (m, 1H). The mixture of isomers of 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid (23 mg) were separated by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 60% CO₂, 40% iPrOH) to afford two enantiomers. The first eluting enantiomer (5 mg) was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₁N₅O₆S, 647.28; m/z found, 648.3 [M+H]⁺.

Example 421: (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting enantiomer (5 mg) from the chiral separation described in Example 420 was designated (*R): MS (ESI): mass calcd. for C₃₄H₄₁N₅O₆S, 647.28; m/z found, 648.3 [M+H]⁺.

Example 422: (*S)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Thionyl chloride (200 mg, 1.69 mmol) was added to methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 48, 218 mg, 0.5 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure providing methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. A mixture of (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 10, 142 mg, 0.500 mmol), methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (229 mg, 0.500 mmol) and iPr₂NEt (0.5 mL) was stirred and heated at 150° C. for 16 hours. The mixture was concentrated. The residue was re-dissolved into pyridine (2 mL). Lithium iodide (30 mg, 0.224 mmol) was added. The mixture was heated at 150° C. for 5 hours. The mixture was concentrated. Water (20 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (30 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (20% methanol/CH₂Cl₂) to provide 3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (94 mg, 27%). MS (ESI): mass calcd. for C₃₃H₃₄F₃N₇O₄S, 681.23; m/z found, 682.2 [M+H]⁺. The mixture of isomers of 3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (94 mg) were separated by chiral SFC (stationary phase: IG 2×25 cm, mobile phase: 70% CO₂, 30% EtOH) to afford two diastereomers. The first eluting diastereomer (41 mg) was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₄F₃N₇O₄S, 681.23; m/z found, 682.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.51 (d, J=2.1 Hz, 1H), 8.34 (d, J=7.0 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 7.48 (d, J=7.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 4.57-4.39 (m, 2H), 4.33-4.13 (m, 2H), 3.34 (s, 1H), 3.30-3.10 (m, 3H), 2.72 (s, 3H), 2.20 (s, 3H), 1.75-1.53 (m, 3H), 1.47-1.29 (m, 9H).

Example 423: (*R)-3-(3-(((*R)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting diastereomer (35 mg) from the chiral separation described in Example 422 was designated (*R): MS (ESI): for C₃₃H₃₄F₃N₇O₄S, 681.23; m/z found, 682.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.51 (d, J=2.1 Hz, 1H), 8.36 (d, J=7.0 Hz, 1H), 8.26 (d, J=2.1 Hz, 1H), 7.49 (d, J=7.0 Hz, 1H), 7.31-7.22 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 4.60-4.52 (m, 1H), 4.43 (d, J=14.6 Hz, 1H), 4.31-4.22 (m, 2H), 3.34 (s, 1H), 3.32-3.18 (m, 3H), 2.71 (s, 3H), 2.20 (s, 3H), 1.79-1.61 (m, 2H), 1.59-1.21 (m, 10H).

Example 424: (*S)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Thionyl chloride (200 mg, 1.69 mmol) was added to methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 48, 218 mg, 0.5 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure providing methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. A mixture of (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 11, 142 mg, 0.500 mmol), methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (229 mg, 0.500 mmol) and iPr₂NEt (0.5 mL) in CH₃CN (3 mL) was heated at 150° C. for 16 hours and then the mixture was concentrated. The residue was re-dissolved into pyridine (2 mL) and lithium iodide (30 mg, 0.224 mmol) was added. The mixture was heated at 150° C. for 5 hours. The mixture was concentrated. Water (20 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (30 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (20% methanol/CH₂Cl₂) to provide 3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (100 mg, 29%). MS (ESI): mass calcd. for C₃₃H₃₄F₃N₇O₄S, 681.23; m/z found, 682.2 [M+H]⁺. The mixture of 3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (100 mg) were separated by chiral SFC (stationary phase: AD-H 2×25 cm, mobile phase: 15-24% isopropanol (0.1% diethylamine)/CO₂) to afford two diastereomers. The first eluting diastereomer (55 mg) was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₄F₃N₇O₄S, 681.23; m/z found, 682.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.03 (d, J=6.7 Hz, 1H), 7.34-7.27 (m, 2H), 7.17-7.07 (m, 2H), 4.80 (s, 1H), 4.71-4.62 (m, 1H), 4.49 (d, J=15.0 Hz, 1H), 4.42-4.34 (m, 1H), 4.14 (d, J=15.0 Hz, 1H), 3.50-3.18 (m, 4H), 2.71 (s, 3H), 2.21 (s, 3H), 1.86-1.62 (m, 3H), 1.58-1.46 (m, 3H), 1.43-1.30 (m, 6H).

Example 425: (*R)-3-(3-(((*S)-3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting diastereomer (35 mg) from the chiral separation described in Example 424 was designated (*R): mass calcd. for C₃₃H₃₄F₃N₇O₄S, 681.23; m/z found, 682.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.17-7.07 (m, 2H), 4.82 (s, 1H), 4.69-4.60 (m, 1H), 4.52 (d, J=14.8 Hz, 1H), 4.40-4.26 (m, 1H), 4.09 (d, J=14.8 Hz, 1H), 3.48 (s, 1H), 3.38-3.12 (m, 3H), 2.71 (s, 3H), 2.23 (s, 3H), 1.83-1.58 (m, 3H), 1.56-1.32 (m, 9H).3.50-3.18 (m, 4H), 2.71 (s, 3H), 2.21 (s, 3H), 1.86-1.62 (m, 3H), 1.58-1.46 (m, 3H), 1.43-1.30 (m, 6H).

Example 426: (S)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b)][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

Step A: (3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylphenyl)(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. A solution of nBuLi (0.700 mL, 2.5 M in hexanes, 1.75 mmol) was added dropwise at −78° C. to ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 312 mg, 0.99 mmol) in THF (40 mL). The resulting mixture was stirred for 1 hour. 7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (Intermediate 164, 227 mg, 0.99 mmol) in THF (5 mL) was added dropwise and the resulting solution was warmed to room temperature over a period of 4 hours. The mixture was quenched with aqueous saturated NH₄Cl solution (20 mL) and the aqueous layer was extracted with EtOAc (30 mL×2). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure to provide the title compound (329 mg, 71.6%). MS (ESI): mass calcd. for C₂₃H₃₁F₂N₃O₃Si, 463.6; m/z found, 464.2 [M+H]⁺.

Step B: Methyl (S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. 2,2,2-Trichloroacetonitrile (266 mg, 1.85 mmol) and DBU (5 uL, 0.0330 mmol) were added to (3-(((tert-butyldimethyl silyl)oxy)methyl)-4-methylphenyl)(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (329 mg, 0.710 mmol) in acetonitrile (5 mL) at room temperature, and the mixture was stirred for 45 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (294 mg, 1.68 mmol) and bis(trifluoromethanesulfonyl)imide (21.0 mg, 0.070 mmol) were then added sequentially, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with aqueous saturated NaHCO₃ solution (20 mL), and extracted with DCM (50 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was dissolved in DCM (10 mL) and SOCl₂ (0.257 mL, 3.54 mmol) was added and stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by flash column chromatography (10% EtOAc/Hexanes) to provide the title compound (250 mg, 57%). MS (ESI): mass calcd. for C₂₂H₂₄ClF₂N₃O₃, 451.9; m/z found, 452.1 [M+H]⁺.

Step C: (*S)-3-(7-(difluoromethoxy)-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid. A mixture of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 89 mg, 0.33 mmol), methyl (S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (148 mg, 0.33 mmol) and iPr₂NEt (0.5 mL) was stirred and heated at 150° C. for 16 hours. The mixture was concentrated. LiOH (3M, 1 mL) was added to the residue in THF (1 mL) and MeOH (1 mL), The mixture was heated at 70° C. for 8 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide 3-(7-(difluoromethoxy)-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid (46 mg, 21%). MS (ESI): mass calcd. for C₃₂H₃₅F₂N₅O₇S, 671.22; m/z found, 672.2 [M+H]⁺. The mixture of 3-(7-(difluoromethoxy)-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid (46 mg) were separated by chiral SFC (stationary phase: IG 2×25 cm, mobile phase: 20% Methanol(0.1% NPA)/CO₂) to afford two enantiomers.

The first eluting enantiomer (12 mg) was designated (*S): MS (ESI): mass calcd. for C₃₂H₃₅F₂N₅O₇S, 671.22; m/z found, 672.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.61-8.40 (m, 1H), 8.26-8.12 (m, 1H), 7.84 (s, 1H), 7.23-6.91 (m, 5H), 6.49-6.85 (m, 1H), 4.66-4.30 (m, 6H), 4.01-3.88 (m, 2H), 3.55-3.39 (m, 4H), 2.23 (s, 3H), 1.61-0.74 (m, 10H).

Example 427: (R*)-3-(7-(difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting enantiomer (12 mg) from the chiral separation described in Example 426 was designated (*R): MS (ESI): mass calcd. for C₃₂H₃₅F₂N₅O₇S, 671.22; m/z found, 672.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.61-8.40 (m, 1H), 8.25-8.08 (m, 1H), 7.87 (s, 1H), 7.25-7.01 (m, 5H), 6.49-6.85 (m, 1H), 4.62-4.35 (m, 6H), 3.98-3.84 (m, 2H), 3.58-3.33 (m, 4H), 2.24 (s, 3H), 1.60-0.74 (m, 10H).

Example 428: (S*)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

Step A: (5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol. A solution of n-BuLi (4.8 mL, 2.5 M in Hexanes, 12 mmol) was added dropwise at −78° C. to ((5-bromo-2-methylbenzyl)oxy)(tert-butyl)dimethylsilane (Intermediate 19, 2.93 g, 9.29 mmol) in THF (120 mL). The resulting mixture was stirred for 1 hour. 1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehyde (Intermediate 119, 2.00 g, 9.29 mmol) in THF (10 mL) was added dropwise and the resulting solution was warmed to room temperature over a period of 4 hours. The mixture was quenched with aqueous saturated NH₄Cl solution (100 mL) and the aqueous layer was extracted with EtOAc (100 mL×2). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc/Hexanes) providing the title compound (2.60 g, 61.8%). MS (ESI): mass calcd. for C₂₅H₃₆N₄O₂Si, 452.26; m/z found, 453.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=2.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.35-6.17 (m, 1H), 4.74 (s, 1H), 4.61 (s, 2H), 4.53-4.39 (m, 2H), 2.70 (s, 3H), 2.38 (s, 3H), 1.46-1.32 (m, 1H), 0.81 (s, 9H), 0.69-0.58 (m, 2H), 0.53-0.43 (m, 2H), 0.00 (s, 6H).

Step B: methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. 2,2,2-Trichloroacetonitrile (1.08 g, 7.48 mmol) and DBU (20.3 □L, 0.136 mmol) were added to (5-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-3-yl)(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanol (1.08 g, 2.87 mmol) in acetonitrile (30 mL) at room temperature, and the mixture was stirred for 45 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (1.19 g, 6.83 mmol) and bis(trifluoromethanesulfonyl)imide (87.0 mg, 0.31 mmol) were then added sequentially, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with aqueous saturated NaHCO₃ solution (20 mL), and extracted with DCM (50 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was dissolved in DCM (20 mL) and SOCl₂ (1.04 mL, 14.3 mmol) was added and stirred at room temperature for 2 hours. The mixture was concentrated and the residue was purified by flash column chromatography (10% EtOAc/Hexanes) to provide the title compound (394 mg, 31.1%). MS (ESI): mass calcd. for C₂₄H₂₉ClN₄O₂, 440.2; m/z found, 441.2 [M+H]⁺.

Step C: (*S)-3-(1-(cyclopropylmethyl)-4,7-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid A mixture of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 92 mg, 0.34 mmol), methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (394 mg, 0.894 mmol) and iPr₂NEt (0.5 mL) was stirred and heated at 150° C. for 16 hours. The mixture was concentrated. LiOH (3M, 1 mL) was added to the residue in THF (1 mL) and MeOH (1 mL), The mixture was heated at 70° C. for 8 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide 3-(1-(cyclopropylmethyl)-4,7-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid (40 mg, 18%). MS (ESI): mass calcd. for C₃₂H₃₅F₂N₅O₇S, 671.22; m/z found, 672.2 [M+H]⁺. The mixture of 3-(7-(difluoromethoxy)-1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid (40 mg) were separated by chiral SFC (stationary phase: AD-H 2×25 cm, mobile phase: 30% Methanol(0.2% NPA)/CO₂) to afford two enantiomers. The first eluting enantiomer (12 mg) was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₀N₆O₆S, 660.27; m/z found, 661.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.47 (dd, J=4.9, 1.9 Hz, 1H), 8.36 (s, 1H), 8.21 (dd, J=7.6, 1.9 Hz, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.38 (dd, J=7.6, 4.9 Hz, 1H), 5.03 (s, 1H), 4.63-4.40 (m, 3H), 3.97-3.88 (m, 1H), 3.54-3.33 (m, 3H), 2.73 (s, 3H), 2.43 (s, 3H), 1.54-1.22 (m, 13H), 0.67-0.58 (m, 2H), 0.55-0.46 (m, 2H).

Example 429: (R*)-3-(1-(cyclopropylmethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting enantiomer (13 mg) from the chiral separation described in Example 428 was designated (*R): MS (ESI): mass calcd. for C₃₄H₄₀N₆O₆S, 660.27; m/z found, 661.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.47 (dd, J=4.9, 1.9 Hz, 1H), 8.36 (s, 1H), 8.21 (dd, J=7.6, 2.0 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.38 (dd, J=7.7, 4.9 Hz, 1H), 5.07-4.94 (m, 1H), 4.59-4.42 (m, 3H), 3.97-3.85 (m, 1H), 3.55-3.33 (m, 3H), 2.73 (s, 3H), 2.43 (s, 3H), 1.54-1.25 (m, 13H), 0.68-0.56 (m, 2H), 0.55-0.44 (m, 2H).

Example 430: (*S)-3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Thionyl chloride (200 mg, 1.69 mmol) was added to methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 48, 218 mg, 0.5 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure providing methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. A mixture of 4,4-dimethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 82, 784 mg, 0.34 mmol), methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (226 mg, 0.500 mmol) and iPr₂NEt (0.5 mL) in CH₃CN (3 mL) was stirred and heated at 150° C. for 16 hours. The mixture was concentrated. LiOH (3M, 1 mL) was added to the residue in THF (1 mL) and MeOH (1 mL), The mixture was heated at 70° C. for 8 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide 3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (380 mg) MS (ESI): mass calcd. for C₃₀H₃₂F₃N₅O₅S, 631.21; m/z found, 632.2 [M+H]⁺. The mixture of (3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (380 mg) were separated by chiral SFC (stationary phase: Chiralpak IG 5 μm 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two enantiomers. The first eluting enantiomer (61 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₂F₃N₅O₅S, 631.21; m/z found, 632.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.52-8.38 (m, 1H), 8.20-8.10 (m, 1H), 7.98 (d, J=7.1 Hz, 1H), 7.41-7.19 (m, 3H), 7.07-6.94 (m, 2H), 6.46-6.26 (m, 1H), 4.84 (s, 1H), 4.57-4.29 (m, 2H), 3.66-3.46 (m, 2H), 2.70 (s, 3H), 2.17 (s, 3H), 1.33-1.16 (m, 12H).

Example 431: (*R)-3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (56 mg) from the chiral separation described in Example 430 was designated (*R): mass calcd. for C₃₀H₃₂F₃N₅O₅S, 631.21; m/z found, 632.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.55-8.33 (m, 1H), 8.19-8.12 (m, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.38-7.22 (m, 3H), 7.07-6.94 (m, 2H), 6.78-6.57 (m, 1H), 4.84 (s, 1H), 4.56-4.29 (m, 2H), 3.66-3.46 (m, 2H), 2.71 (s, 3H), 2.19 (s, 3H), 1.41-1.15 (m, 12H).

Example 432: (*S)-3-(3-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Thionyl chloride (50 mg, 0.42 mmol) was added to ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 120 mg, 0.285 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. iPr₂NEt (0.5 mL) was added to a mixture of 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 95 mg, 0.35 mmol) and ethyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate in CH₃CN (3 mL). The mixture was stirred at 150° C. for 16 hours. The mixture was concentrated under reduced pressure. NaOH (1M, 2 mL) was added to the residue in THF (2 mL) and the mixture was stirred at RT for 24 hours. Water (5 mL) was added, and the pH of the mixture was adjusted to 3-4 by adding 1 M aqueous HCl solution. The aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by flash column chromatography (10% methanol/CH₂Cl₂) to provide the title compound (72 mg, 39%). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₆S, 645.19; m/z found, 645.9 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.49 (dd, J=4.9, 1.9 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.27-8.15 (m, 1H), 7.46-7.29 (m, 2H), 7.26-7.18 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 5.09-4.97 (m, 1H), 4.60-4.39 (m, 2H), 3.91-3.71 (m, 2H), 3.49-3.34 (m, 3H), 3.28-3.18 (m, 1H), 3.06-2.88 (m, 2H), 2.85-2.75 (s, 3H), 2.31-2.21 (s, 3H), 1.57-1.44 (m, 2H), 1.33-1.15 (m, 2H).

Example 433: (*S)-2,2-difluoro-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Thionyl chloride (200 mg, 1.69 mmol) was added to ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 519 mg, 1.23 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. iPr₂NEt (0.5 mL) was added to a mixture of 8-fluoro-2,2′,3,3′,5′,6′-hexahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran] 1,1-dioxide (Intermediate 165, 352 mg, 1.23 mmol) and ethyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (540 mg, 1.23 mmol) in CH₃CN (3 mL). The mixture was stirred at 150° C. for 16 hours. The mixture was concentrated under reduced pressure providing the title compound (650 mg, 94.1%). MS (ESI): mass calcd. for C₃₃H₃₄F₄N₄O₆S, 690.21; m/z found, 690.8 [M+H]⁺.

Step B: (*S)-2,2-difluoro-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The mixture of ethyl (*S)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (300 mg, 0.434 mmoL) in THF (2 mL) was cooled to −78° C. Then LDA (1.17 mL, 1.17 mmol, 1 M in hexane/THF) was added. The reaction was then stirred at −78° C. for 30 min and followed by addition of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (301 mg, 0.956 mmol). The reaction was then stirred for 15 min at −78° C. and then removed from acetone/dry ice bath and allowed to warm to room temperature. The mixture was then stirred at this temperature for 2 hours. The reaction was quenched with saturated NH₄Cl (5 mL), and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated. The residue was purified by preparative TLC (10% methanol/CH₂Cl₂) to provide the title compound (35 mg, 12%). MS (ESI): mass calcd. for C₃₁H₂₈F₆N₄O₆S, 698.64; m/z found, 699.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) □ 8.25 (d, J=7.3 Hz, 1H), 7.46-7.15 (m, 6H), 7.07 (d, J=7.8 Hz, 1H), 5.37-5.21 (m, 1H), 4.49-4.34 (m, 2H), 3.60-3.44 (m, 2H), 3.23-3.14 (m, 4H), 2.65 (s, 3H), 2.15 (s, 3H), 1.53-1.35 (m, 2H), 1.25-1.04 (m, 2H).

Example 434: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate. To a solution of ethyl (E)-3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)acrylate (Intermediate 174 2.00 g, 8.15 mmol) in a mixture of 1,4-dioxane (56 mL) and water (deionized, 27 mL) was added sequentially (3-(hydroxymethyl)-4-methylphenyl)boronic acid (2.05 g, 12.3 mmol), Et₃N (1.72 mL, 12.3 mmol), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (207 mg, 12.3 mmol). The reaction vessel was evacuated and back-filled with Ar. The mixture was heated in an oil bath at 95° C. for 50 minutes. The reaction mixture was partitioned between EtOAc and water (25 mL each). The aqueous phase was extracted with EtOAc (2×25 mL). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (2.70 g, 90%) as a light tan foam. MS (ESI): mass calcd. for C₂₁H₂₅N₃O₃, 367.2; m/z found, 368.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (s, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 6.97 (dd, J=7.7, 2.1 Hz, 1H), 6.35 (s, 1H), 4.74-4.60 (m, 3H), 4.12-4.05 (m, 2H), 3.65 (s, 1H), 3.63 (s, 3H), 3.15 (dd, J=16.0, 8.9 Hz, 1H), 2.96 (dd, J=16.0, 6.7 Hz, 1H), 2.70 (s, 3H), 2.25 (s, 3H), 1.16 (t, J=7.1 Hz, 3H).

Step B: Ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate. A solution of ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (450 mg, 1.23 mmol), (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 293 mg, 1.23 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (8 mL) was stirred at room temperature for 1 minute. DBAD (423 mg, 1.84 mmol) was added and the solution was stirred at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (650 mg, 90%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.3; m/z found, 589.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.27 (m, 1H), 8.06 (dt, J=7.7, 2.1 Hz, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.17-7.01 (m, 3H), 6.86-6.78 (m, 1H), 6.36 (dd, J=6.8, 0.8 Hz, 1H), 5.30 (s, 1H), 4.72 (td, J=7.8, 2.4 Hz, 1H), 4.49-4.31 (m, 2H), 4.22-4.01 (m, 3H), 3.80-3.42 (m, 4H), 3.29-3.10 (m, 2H), 2.99-2.90 (m, 1H), 2.77 (d, J=3.0 Hz, 4H), 2.28 (d, J=17.6 Hz, 3H), 2.03-1.73 (m, 2H), 1.50-1.32 (m, 2H), 1.31-1.13 (m, 3H).

Step C: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (650 mg, 1.10 mmol), 1 M aqueous NaOH solution (10.0 mL, 10.0 mmol), THF (10 mL) and ethanol (0.65 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4.

Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (598 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₂₉H₃₂N₆O₄S, 560.2; m/z found, 561.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 11.31 (s, 2H), 8.28 (dt, J=4.4, 2.0 Hz, 1H), 8.06-7.99 (m, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.22-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.80 (dd, J=7.7, 4.8 Hz, 1H), 6.69 (d, J=3.4 Hz, 1H), 4.87-4.77 (m, 1H), 4.55 (s, 1H), 4.37 (dd, J=14.7, 3.5 Hz, 1H), 4.20-4.09 (m, 1H), 3.73 (d, J=6.7 Hz, 3H), 3.68-3.53 (m, 2H), 3.45 (s, 1H), 3.36-3.24 (m, 2H), 3.08-3.00 (m, 1H), 2.92-2.78 (m, 4H), 2.24 (d, J=12.9 Hz, 3H), 1.99-1.91 (m, 1H), 1.88-1.74 (m, 1H).

Example 435: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 434, 598 mg) was separated by chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 250×20 mm, isocratic mobile phase: 70% CO₂, 30% MeOH (0.3% iPrNH₂)) to afford two diastereomers. The first eluting isomer (276 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₃₂N₆O₄S, 560.2; m/z found, 561.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 11.31 (s, 2H), 8.28 (dt, J=4.4, 2.0 Hz, 1H), 8.06-7.99 (m, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.22-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.80 (dd, J=7.7, 4.8 Hz, 1H), 6.69 (d, J=3.4 Hz, 1H), 4.82 (td, J=8.5, 5.8 Hz, 1H), 4.55 (s, 1H), 4.37 (dd, J=14.7, 3.5 Hz, 1H), 4.15 (dd, J=19.4, 14.8 Hz, 1H), 3.73 (d, J=6.7 Hz, 3H), 3.66-3.47 (m, 2H), 3.45 (s, 1H), 3.36-3.24 (m, 2H), 3.09-3.00 (m, 1H), 2.92-2.78 (m, 4H), 2.24 (d, J=12.9 Hz, 3H), 1.99-1.90 (m, 1H), 1.88-1.74 (m, 1H).

Example 436: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (300 mg) from the chiral separation described in Example 435 was designated (*R). MS (ESI): mass calcd. for C₂₉H₃₂N₆O₄S, 560.2; m/z found, 561.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 11.31 (s, 2H), 8.28 (dt, J=4.4, 2.0 Hz, 1H), 8.06-7.99 (m, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.22-7.14 (m, 1H), 7.12-6.99 (m, 2H), 6.80 (dd, J=7.7, 4.8 Hz, 1H), 6.69 (d, J=3.4 Hz, 1H), 4.82 (td, J=8.5, 5.8 Hz, 1H), 4.55 (s, 1H), 4.37 (dd, J=14.7, 3.5 Hz, 1H), 4.15 (dd, J=19.4, 14.8 Hz, 1H), 3.73 (d, J=6.7 Hz, 3H), 3.69-3.59 (m, 2H), 3.45 (s, 1H), 3.36-3.24 (m, 2H), 3.14-3.04 (m, 1H), 2.92-2.78 (m, 4H), 2.24 (d, J=12.9 Hz, 3H), 1.97-1.77 (m, 1H), 1.88-1.74 (m, 1H).

Example 437: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate. A solution of ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 434, Step A, 450 mg, 1.23 mmol), (S)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 75, 293 mg, 1.23 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (8 mL) was stirred at room temperature for 1 minute. DBAD (423 mg, 1.84 mmol) was added and the solution was stirred at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (650 mg, 90%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₄S, 588.3; m/z found, 589.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.20 (m, 1H), 8.06 (dt, J=7.7, 2.1 Hz, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.17-7.01 (m, 3H), 6.88-6.82 (m, 1H), 6.36 (dd, J=6.8, 0.8 Hz, 1H), 5.30 (s, 1H), 4.72 (td, J=7.8, 2.4 Hz, 1H), 4.45-4.35 (m, 2H), 4.22-4.01 (m, 3H), 3.80-3.42 (m, 4H), 3.29-3.10 (m, 2H), 2.99-2.89 (m, 1H), 2.77 (d, J=3.0 Hz, 4H), 2.28 (d, J=17.6 Hz, 3H), 2.03-1.73 (m, 2H), 1.50-1.32 (m, 2H), 1.31-1.13 (m, 3H).

Step B: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (650 mg, 1.10 mmol), 1 M aqueous NaOH solution (10.0 mL, 10.0 mmol), THF (10 mL) and ethanol (0.65 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (600 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₂₉H₃₂N₆O₄S, 560.2; m/z found, 561.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (dt, J=4.8, 1.8 Hz, 1H), 8.04 (dt, J=7.7, 1.5 Hz, 1H), 7.45 (d, J=3.7 Hz, 1H), 7.17-6.97 (m, 3H), 6.79 (dd, J=7.7, 4.8 Hz, 1H), 6.53 (d, J=3.0 Hz, 1H), 4.78 (dt, J=8.3, 5.4 Hz, 1H), 4.52 (d, J=11.5 Hz, 1H), 4.37 (dd, J=14.5, 12.3 Hz, 1H), 4.19-4.03 (m, 1H), 3.74-3.44 (m, 6H), 3.30-3.17 (m, 2H), 3.01 (dd, J=16.2, 6.1 Hz, 1H), 2.90-2.72 (m, 1H), 2.68 (d, J=4.0 Hz, 3H), 2.25 (d, J=13.8 Hz, 3H), 1.98-1.90 (m, 2H), 1.84-1.62 (m, 1H), 1.57-1.34 (m, 1H).

Example 438: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 437, 600 mg) was separated by chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 60% CO₂, 40% MeOH (0.3% iPrNH₂)) to afford two diastereomers. The first eluting isomer (276 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₃₂N₆O₄S, 560.2; m/z found, 561.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (dd, J=4.8, 1.8 Hz, 1H), 8.03 (dd, J=7.8, 1.9 Hz, 1H), 7.35 (s, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.08-6.96 (m, 2H), 6.80 (dd, J=7.7, 4.7 Hz, 1H), 6.38 (s, 1H), 4.70 (t, J=7.5 Hz, 1H), 4.45 (s, 1H), 4.34 (d, J=14.8 Hz, 1H), 4.13 (d, J=14.9 Hz, 1H), 3.74-3.61 (m, 5H), 3.68-3.60 (m, 1H), 3.17 (dd, J=13.4, 3.5 Hz, 1H), 3.01 (dd, J=16.0, 8.8 Hz, 2H), 2.88-2.72 (m, 1H), 2.68 (s, 3H), 2.21 (s, 3H), 1.96-1.72 (m, 3H), 1.44-1.39 (m, 1H).

Example 439: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (293 mg) from the chiral separation described in Example 438 was designated (*R). MS (ESI): mass calcd. for C₂₉H₃₂N₆O₄S, 560.2; m/z found, 561.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J=4.8, 1.9 Hz, 1H), 8.04 (dd, J=7.8, 1.8 Hz, 1H), 7.40 (s, 1H), 7.06 (d, J=6.2 Hz, 3H), 6.80 (dd, J=7.8, 4.8 Hz, 1H), 6.67 (s, 3H), 6.39 (s, 1H), 4.70 (t, J=7.4 Hz, 1H), 4.56 (t, J=10.7 Hz, 1H), 4.40 (d, J=14.3 Hz, 1H), 4.03 (d, J=14.4 Hz, 1H), 3.75-3.65 (m, 4H), 3.56 (td, J=10.7, 5.7 Hz, 1H), 3.47 (dd, J=11.5, 6.1 Hz, 1H), 3.27 (dd, J=13.4, 3.8 Hz, 1H), 3.08 (s, 1H), 2.99 (s, 1H), 2.72 (s, 3H), 2.25 (s, 3H), 2.02-1.87 (m, 1H), 1.63 (p, J=6.0 Hz, 1H).

Example 440: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate. A solution of ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 434, Step A, 400 mg, 1.09 mmol), (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2, 260 mg, 1.03 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (8 mL) was stirred at room temperature for 1 minute. DBAD (428 mg, 1.63 mmol) was added and the solution was stirred at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (650 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₈N₆O₄S, 602.2; m/z found, 603.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.29-8.20 (m, 1H), 8.09-8.00 (m, 1H), 7.44 (d, J=6.4 Hz, 2H), 7.23-6.99 (m, 3H), 6.80 (td, J=7.4, 4.6 Hz, 1H), 6.40 (d, J=11.9 Hz, 1H), 4.75 (t, J=7.7 Hz, 1H), 4.52-4.47 (m, 2H), 4.26-4.00 (m, 5H), 3.76 (d, J=2.8 Hz, 3H), 3.30-2.91 (m, 5H), 2.76 (d, J=6.1 Hz, 3H), 2.31-2.21 (m, 3H), 1.71-1.54 (m, 2H), 1.45-1.30 (m, 2H), 1.20-1.15 (m, 3H).

Step B: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. A mixture of ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate (650 mg, 1.08 mmol), 1 M aqueous NaOH solution (10.0 mL, 10.0 mmol), THF (10 mL) and ethanol (0.65 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (612 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 3H), 8.28 (td, J=4.4, 1.8 Hz, 1H), 8.00 (dt, J=7.7, 1.5 Hz, 1H), 7.64 (s, 1H), 7.18-6.99 (m, 3H), 6.89-6.80 (m, 1H), 6.69 (s, 1H), 4.88-4.80 (m, 1H), 4.55-4.36 (m, 2H), 4.28-4.10 (m, 2H), 3.74 (d, J=3.4 Hz, 3H), 3.36-2.99 (m, 5H), 2.81 (d, J=3.2 Hz, 3H), 2.23 (d, J=11.5 Hz, 3H), 1.81-1.58 (m, 2H), 1.50-1.30 (m, 2H).

Example 441: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid (Example 440, 612 mg) was separated by chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 250×20 mm, isocratic mobile phase: 70% CO₂, 30% MeOH (0.3% iPrNH₂)) to afford two diastereomers. The first eluting isomer (291 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J=4.6, 1.9 Hz, 1H), 8.00 (dd, J=7.8, 1.9 Hz, 1H), 7.35 (s, 1H), 7.11 (d, J=1.7 Hz, 1H), 7.09-7.00 (m, 2H), 6.81 (dd, J=7.8, 4.7 Hz, 1H), 6.63 (s, 1H), 6.38 (s, 1H), 5.30 (s, 1H), 4.69 (dd, J=8.9, 6.2 Hz, 1H), 4.38 (dd, J=15.5, 8.1 Hz, 2H), 4.20 (dt, J=13.3, 4.9 Hz, 1H), 4.14 (d, J=15.0 Hz, 1H), 3.71 (s, 3H), 3.29-3.20 (m, 1H), 3.12 (dd, J=13.5, 11.8 Hz, 1H), 3.06 (dd, J=13.5, 3.9 Hz, 1H), 3.03-2.89 (m, 2H), 2.75 (dd, J=15.7, 6.2 Hz, 1H), 2.69 (s, 3H), 2.20 (s, 3H), 1.65 (dt, J=13.0, 5.4 Hz, 1H), 1.58-1.42 (m, 2H), 1.34-1.26 (m, 1H).

Example 442: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (299 mg) from the chiral separation described in Example 441 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.7; m/z found, 575.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.27 (dd, J=4.6, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.9 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J=3.8 Hz, 3H), 6.94 (s, 1H), 6.85 (s, 1H), 6.80 (dd, J=7.8, 4.6 Hz, 1H), 6.38 (s, 1H), 5.31 (s, 1H), 4.71 (t, J=7.5 Hz, 1H), 4.48 (dd, J=19.8, 13.2 Hz, 2H), 4.17 (dt, J=13.2, 4.8 Hz, 1H), 4.01 (d, J=14.4 Hz, 1H), 3.73 (s, 3H), 3.19 (dd, J=13.5, 3.7 Hz, 1H), 3.10-2.92 (m, 4H), 2.78-2.71 (m, 1H), 2.72 (s, 3H), 2.25 (s, 3H), 1.65-1.53 (m, 2H), 1.32-1.17 (m, 1H).

Example 443: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate. A solution of ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 434, Step A, 400 mg, 1.09 mmol), (*R)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 3, 260 mg, 1.03 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (8 mL) was stirred at room temperature for 1 minute. DBAD (428 mg, 1.63 mmol) was added and the solution was stirred at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (600 mg, 91%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₈N₆O₄S, 602.3; m/z found, 603.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.20 (m, 1H), 8.08-7.97 (m, 1H), 7.73-7.63 (m, 1H), 7.59-7.38 (m, 1H), 7.20-7.01 (m, 3H), 6.80 (dt, J=7.8, 4.8 Hz, 1H), 6.39 (d, J=6.9 Hz, 1H), 4.74 (t, J=7.7 Hz, 1H), 4.56-4.36 (m, 2H), 4.26-4.00 (m, 4H), 3.76 (d, J=1.5 Hz, 3H), 3.29-2.91 (m, 5H), 2.76 (d, J=4.0 Hz, 3H), 2.33-2.22 (m, 3H), 1.80-1.12 (m, 8H).

Step B: 3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. A mixture of ethyl 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate (600 mg, 1.08 mmol), 1 M aqueous NaOH solution (9.2 mL, 9.2 mmol), THF (9.2 mL) and ethanol (0.58 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (560 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 2H), 8.29-8.00 (m, 1H), 8.01 (dt, J=7.8, 1.6 Hz, 1H), 7.44 (d, J=4.3 Hz, 1H), 7.18-7.00 (m, 3H), 6.86-6.79 (m, 1H), 6.53 (s, 1H), 5.30 (s, 1H), 4.80 (dt, J=10.1, 5.4 Hz, 1H), 4.53-4.35 (m, 2H), 4.24-4.03 (m, 2H), 3.72 (d, J=4.4 Hz, 3H), 3.30-2.96 (m, 4H), 2.68 (d, J=7.4 Hz, 3H), 2.24 (d, J=17.4 Hz, 3H), 1.77-1.43 (m, 2H), 1.41 (s, 1H), 1.38 (s, 2H).

Example 444: (*S)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3,7-dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid (Example 443, 516 mg) was separated by chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 250×20 mm, isocratic mobile phase: 70% CO₂, 30% MeOH (0.3% iPrNH₂)) to afford two diastereomers. The first eluting isomer (269 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (dd, J=4.6, 1.9 Hz, 1H), 7.99 (dd, J=7.8, 1.9 Hz, 1H), 7.35 (s, 1H), 7.10-7.03 (m, 3H), 6.81 (s, 1H), 6.79 (dd, J=7.8, 4.6 Hz, 1H), 6.38 (s, 1H), 5.30 (s, 1H), 4.70 (dd, J=8.6, 6.4 Hz, 1H), 4.53-4.41 (m, 2H), 4.16 (dt, J=13.2, 4.7 Hz, 1H), 4.00 (d, J=14.4 Hz, 1H), 3.72 (s, 3H), 3.17 (dd, J=13.5, 3.8 Hz, 1H), 3.04 (t, J=12.9 Hz, 1H), 3.01-2.91 (m, 3H), 2.76-2.68 (m, 1H), 2.71 (s, 3H), 2.24 (s, 3H), 1.63-1.52 (m, 1H), 1.42-1.30 (m, 1H), 1.35 (s, 1H), 1.33-1.23 (m, 1H).

Example 445: (*R)-3-(3,7-Dimethyl-7H-pyrrolo[2,3-c]pyridazin-6-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (266 mg) from the chiral separation described in Example 444 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₄N₆O₄S, 574.2; m/z found, 575.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.27 (dd, J=4.6, 1.8 Hz, 1H), 8.00 (dd, J=7.8, 1.9 Hz, 1H), 7.36 (s, 1H), 7.07 (d, J=3.8 Hz, 3H), 6.94 (s, 1H), 6.85 (s, 1H), 6.80 (dd, J=7.8, 4.6 Hz, 1H), 6.38 (s, 1H), 5.31 (s, 1H), 4.71 (t, J=7.5 Hz, 1H), 4.42-4.34 (m, 2H), 4.17 (dt, J=13.2, 4.8 Hz, 1H), 4.01 (d, J=14.4 Hz, 1H), 3.73 (s, 3H), 3.19 (dd, J=13.5, 3.7 Hz, 1H), 3.10-2.92 (m, 4H), 2.78-2.71 (m, 1H), 2.72 (s, 3H), 2.25 (s, 3H), 1.63-1.57 (m, 2H), 1.32-1.17 (m, 1H).

Example 446: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.32 mL, 1.63 mmol) was added to ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 400 mg, 0.99 mmol), (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2, 357 mg, 1.41 mmol), and triphenylphosphine (386 mg, 1.47 mmol) in THF (11 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (630 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₆F₂N₆O₄S, 638.3 m/z found, 639.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (dd, J=4.7, 1.9 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 8.04 (dd, J=7.8, 1.9 Hz, 1H), 7.24-7.06 (m, 3H), 6.91-6.78 (m, 2H), 4.95 (dt, J=8.9, 6.4 Hz, 1H), 4.61-4.40 (m, 2H), 4.32-4.03 (m, 5H), 3.33-2.96 (m, 5H), 2.83 (d, J=9.5 Hz, 3H), 2.27 (d, J=10.1 Hz, 3H), 2.04 (s, 2H), 1.83-1.33 (m, 4H), 1.34-1.11 (m, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate (630 mg, 0.99 mmol), 1 M aqueous NaOH solution (9.0 mL, 9.0 mmol), THF (9.0 mL) and ethanol (0.06 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (595 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₄S, 610.2 m/z found, 611.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.29 (dd, J=4.7, 1.9 Hz, 1H), 8.15 (d, J=7.1 Hz, 1H), 8.04 (dd, J=7.8, 1.9 Hz, 1H), 7.25-7.09 (m, 3H), 7.13-7.06 (m, 1H), 6.89 (dd, J=10.6, 7.3 Hz, 1H), 6.88-6.80 (m, 1H), 5.00-4.90 (m, 1H), 4.56-4.38 (m, 2H), 4.28-4.07 (m, 4H), 3.32-3.20 (m, 1H), 3.24-3.11 (m, 3H), 3.10-3.00 (m, 1H), 2.77 (d, J=8.3 Hz, 3H), 2.25 (d, J=9.5 Hz, 3H), 2.04 (s, 1H), 1.72-1.52 (m, 2H), 1.45-1.35 (m, 1H).

Example 447: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 446, 595 mg) was separated by chiral SFC (stationary phase: Daicel Chiralpak IC 5 μm 250×30 mm, isocratic mobile phase: 62% CO₂, 38% MeOH (0.3% iPrNH₂)) to afford two diastereomers. The first eluting isomer (297 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₄S, 610.2; m/z found, 611.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 8.29 (dd, J=4.7, 1.9 Hz, 1H), 8.15 (d, J=7.1 Hz, 1H), 8.04 (dd, J=7.8, 1.9 Hz, 1H), 7.24-7.05 (m, 4H), 6.89 (dd, J=10.8, 7.2 Hz, 1H), 6.88-6.80 (m, 1H), 4.95 (q, J=8.0 Hz, 1H), 4.57-4.38 (m, 2H), 4.28-4.07 (m, 3H), 3.31-3.18 (m, 1H), 3.17 (dd, J=10.9, 6.7 Hz, 3H), 3.10-3.00 (m, 1H), 2.77 (d, J=9.2 Hz, 3H), 2.25 (d, J=9.7 Hz, 3H), 2.06 (d, J=11.5 Hz, 1H), 1.65 (s, 1H), 1.72-1.58 (m, 1H), 1.53 (s, 1H), 1.44-1.32 (m, 1H).

Example 448: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (298 mg) from the chiral separation described in Example 446 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₄S, 610.2; m/z found, 611.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (dd, J=4.7, 1.8 Hz, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.94 (dd, J=7.8, 1.8 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.01 (s, 2H), 6.84-6.70 (m, 2H), 5.23 (s, 1H), 5.17-5.12 (m, 5H), 4.84 (s, 1H), 4.48-4.34 (m, 2H), 4.17 (dt, J=13.3, 5.0 Hz, 1H), 4.04 (d, J=14.7 Hz, 1H), 3.22-3.10 (m, 2H), 3.14-3.04 (m, 1H), 2.72 (s, 3H), 2.16 (s, 3H), 1.60 (dd, J=11.0, 5.9 Hz, 1H), 1.59-1.43 (m, 1H), 1.35-1.28 (m, 2H).

Example 449: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6 (7H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6 (7H)-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.45 mL, 2.28 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 550 mg, 1.36 mmol), (R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 4, 457 mg, 1.91 mmol), and triphenylphosphine (529 mg, 2.02 mmol) in THF (10 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (820 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.3; m/z found, 625.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dt, J=4.7, 1.7 Hz, 1H), 8.20-8.12 (m, 1H), 8.08 (dd, J=7.7, 1.8 Hz, 1H), 7.18-7.05 (m, 3H), 6.89-6.77 (m, 2H), 4.99-4.90 (m, 1H), 4.66-4.58 (m, 1H), 4.42 (dd, J=14.6, 6.2 Hz, 1H), 4.25-4.00 (m, 3H), 3.75-3.58 (m, 2H), 3.38-3.30 (m, 1H), 3.13 (dd, J=15.8, 6.9 Hz, 1H), 3.08-2.98 (m, 1H), 2.93-2.78 (m, 4H), 2.28 (d, J=4.0 Hz, 3H), 2.11-1.63 (m, 4H), 1.58-1.43 (m, 1H), 1.30-1.13 (m, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (820 mg, 1.31 mmol), 1 M aqueous NaOH solution (12.0 mL, 12.0 mmol), and THF (12.0 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (778 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₄S, 596.2; m/z found, 597.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (dt, J=4.8, 1.8 Hz, 2H), 8.14 (t, J=6.5 Hz, 1H), 8.07 (dt, J=7.7, 1.8 Hz, 1H), 7.24-7.04 (m, 4H), 6.88 (dd, J=14.0, 7.3 Hz, 1H), 6.85-6.75 (m, 1H), 4.94 (dt, J=9.1, 6.2 Hz, 1H), 4.61 (s, 1H), 4.41 (dd, J=14.6, 6.2 Hz, 1H), 4.23-4.09 (m, 1H), 3.70-3.55 (m, 2H), 3.38-3.30 (m, 1H), 3.19-3.08 (m, 1H), 3.05-2.98 (m, 1H), 2.86 (td, J=12.3, 3.2 Hz, 1H), 2.76 (d, J=6.5 Hz, 3H), 2.26 (d, J=5.0 Hz, 3H), 2.07-1.93 (m, 1H), 1.93-1.77 (m, 1H), 1.79-1.60 (m, 1H), 1.55-1.40 (m, 1H).

Example 450: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 449, 778 mg) was separated by chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 55% CO₂, 45% MeOH) to afford two diastereomers. The first eluting isomer (374 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₄S, 596.2; m/z found, 597.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J=4.8, 1.8 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 8.06 (dd, J=7.7, 1.7 Hz, 1H), 7.20 (s, 1H), 7.17-7.05 (m, 4H), 6.88 (d, J=7.2 Hz, 1H), 6.80 (dd, J=7.8, 4.8 Hz, 1H), 4.95 (dd, J=8.9, 6.7 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 4.41 (d, J=14.5 Hz, 1H), 4.17 (d, J=14.5 Hz, 1H), 3.70 (q, J=7.0 Hz, 1H), 3.61 (dd, J=10.5, 4.7 Hz, 2H), 3.29 (dd, J=13.3, 3.7 Hz, 1H), 3.15 (dd, J=16.0, 6.6 Hz, 1H), 3.04 (dd, J=16.0, 9.0 Hz, 1H), 2.85 (t, J=12.6 Hz, 1H), 2.77 (s, 3H), 2.26 (s, 3H), 1.99-1.90 (m, 1H), 1.85-1.77 (m, 1H), 1.49-1.38 (m, 1H).

Example 451: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (389 mg) from the chiral separation described in Example 450 was designated (*R). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₄S, 596.2; m/z found, 597.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J=4.8, 1.8 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J=1.9 Hz, 1H), 7.15-7.05 (m, 2H), 6.91 (d, J=7.2 Hz, 1H), 6.80 (dd, J=7.7, 4.8 Hz, 1H), 4.97-4.90 (m, 1H), 4.61 (s, 1H), 4.40 (d, J=14.7 Hz, 1H), 4.19 (d, J=14.7 Hz, 1H), 3.75-3.56 (m, 2H), 3.46 (s, 1H), 3.36 (dd, J=13.3, 3.7 Hz, 1H), 3.16 (dd, J=16.0, 6.6 Hz, 1H), 3.05 (dd, J=16.0, 9.0 Hz, 1H), 2.87 (t, J=12.5 Hz, 1H), 2.76 (s, 3H), 2.25 (s, 3H), 2.06-1.94 (m, 1H), 1.92-1.83 (m, 1H), 1.74 (qt, J=11.9, 7.0 Hz, 1H), 1.50 (dd, J=13.5, 5.9 Hz, 1H).

Example 452: 3-(3-((10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: tert-Butyl 2-(((2-chloropyridine)-3-sulfonamido)methyl)-5,5-difluoropiperidine-1-carboxylate. Potassium carbonate (145 mg, 1.05 mmol) was added to a mixture of tert-butyl 2-(aminomethyl)-5,5-difluoropiperidine-1-carboxylate (250 mg, 0.99 mmol), in THF (3.37 mL) and H₂O (0.67 mL). 2-Chloropyridine-3-sulfonyl chloride (212 mg, 0.99 mmol) was then added and the mixture was stirred at room temperature for 6.5 hours. The mixture was concentrated to dryness under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, dried over anhydrous MgSO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (400 mg, 94%) as a white solid. MS (ESI): mass calcd. for C₁₆H₂₂ClF₂N₃O₄S, 425.1; m/z found, 426.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) □ 8.57 (dd, J=4.7, 1.9 Hz, 1H), 8.39 (dd, J=7.8, 1.9 Hz, 1H), 7.45 (dd, J=7.8, 4.8 Hz, 1H), 6.17 (s, 1H), 4.40-4.30 (m, 1H), 3.34-3.25 (m, 1H), 3.05 (dt, J=13.4, 5.7 Hz, 2H), 2.10-1.80 (m, 4H), 1.79-1.70 (m, 1H), 1.47 (s, 9H).

Step B: 10,10-Difluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide. A solution of 20% TFA in DCM (3.27 mL, 42.8 mol) was added to tert-butyl 2-(((2-chloropyridine)-3-sulfonamido)methyl)-5,5-difluoropiperidine-1-carboxylate (400 mg, 0.94 mmol). The resulting mixture was stirred for 2.5 hours at room temperature, then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (250 mg, 92%). MS (ESI): mass calcd. for C₁₁H₁₃F₂N₃O₂S, 289.0 m/z found, 290.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) □ 8.24 (dd, J=4.5, 1.8 Hz, 1H), 7.87 (dt, J=7.8, 1.3 Hz, 1H), 6.82 (dd, J=7.9, 4.6 Hz, 1H), 5.83-5.75 (m, 1H), 4.68-4.60 (m, 1H), 4.33 (dq, J=10.6, 5.2 Hz, 1H), 3.65-3.32 (m, 3H), 2.27-1.96 (m, 3H), 1.77-1.63 (m, 1H).

Step C: Ethyl 3-(3-((10,10-difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.28 mL, 1.42 mmol) was added to a stirring mixture of ethyl 3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 25, 364 mg, 0.84 mmol), 10,10-difluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (250 mg, 0.86 mmol), and triphenylphosphine (336 mg, 1.28 mmol) in THF (9.8 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (500 mg, 84%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₃F₅N₆O₄S, 692.2 m/z found, 693.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J=4.6, 1.8 Hz, 1H), 8.09-8.00 (m, 2H), 7.20-7.08 (m, 3H), 7.01-6.90 (m, 2H), 4.98-4.89 (m, 1H), 4.68-4.61 (m, 1H), 4.50 (d, J=14.6 Hz, 1H), 4.37-4.02 (m, 4H), 3.69-3.58 (m, 1H), 3.36-2.96 (m, 4H), 2.83 (d, J=2.3 Hz, 3H), 2.27 (d, J=6.6 Hz, 1H), 2.14-1.93 (m, 5H), 1.69-1.55 (m, 1H), 1.30-1.13 (m, 3H).

Step D: 3-(3-((10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3434(10,10-difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (500 mg, 0.72 mmol), 1 M aqueous NaOH solution (6.7 mL, 9.0 mmol), and THF (6.7 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (458 mg, 95%) as a white foam. MS (ESI): mass calcd. for C₃₀H₂₉F₅N₆O₄S, 664.2; m/z found, 665.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd, J=4.7, 1.8 Hz, 1H), 8.09 (dt, J=7.8, 1.7 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.18-7.04 (m, 3H), 7.01-6.89 (m, 2H), 4.97-4.88 (m, 1H), 4.60 (td, J=12.5, 5.8 Hz, 1H), 4.48 (d, J=14.8 Hz, 1H), 4.32-4.07 (m, 2H), 3.69-3.58 (m, 1H), 3.29-3.25 (m, 1H), 3.24-3.09 (m, 2H), 3.05 (dt, J=16.3, 8.5 Hz, 1H), 2.77 (s, 3H), 2.26 (d, J=6.4 Hz, 3H), 2.04 (s, 3H), 1.65-1.55 (m, 1H), 1.26 (t, J=7.1 Hz, 1H).

Example 453: (*S)-3-(3-(((*S)-10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 4 diastereomers of 3-(3-((10,10-difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 452, 458 mg) was separated using two chiral separation methods. The mixture of 4 diastereomers was initially subjected to Chiral Separation Method V: chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 60% CO₂, 40% iPrOH) to provide Example 455 and Example 456 and a mixture of the two remaining diastereomers (Example 453 and Example 454). The mixture of Example 453 and Example 454 was subsequently separated using Chiral Separation Method VI: chiral SFC (stationary phase: Lux Cellulose-4 5 μm 250×21.2 mm, Mobile phase: 70% CO₂, 30% EtOH) to afford Example 453 and Example 454. The chiral separation method, order of elution and designated stereochemistry is tabulated below in Table 5. When the stereochemical configuration is written as, for example (*S, *R), with the first configuration, (*S), corresponds to the configuration at the 3-propanoic carbon and the second configuration, (*R), corresponds to the stereochemistry at the sultam. The characterization for (*S)-3-(3-(((*S)-10,10-difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 453, 78 mg) is as follows: MS (ESI): mass calcd. for C₃₀H₂₉F₅N₆O₄S, 664.2; m/z found, 665.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.27 (dd, J=4.7, 1.8 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.14-6.98 (m, 3H), 6.90-6.82 (m, 2H), 4.96 (s, 1H), 4.85 (dd, J=8.9, 6.8 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.42 (d, J=14.8 Hz, 1H), 4.19-4.13 (m, 1H), 4.10 (d, J=14.8 Hz, 1H), 3.69-3.55 (m, 1H), 3.25 (dd, J=13.4, 3.7 Hz, 1H), 3.13-3.01 (m, 2H), 2.98 (dd, J=16.1, 9.0 Hz, 1H), 2.72 (s, 2H), 2.19 (s, 3H), 1.97-1.84 (m, 3H), 1.20-1.07 (m, 2H).

TABLE 5 Chiral separation method, order of elution and esignated stereochemistry for Examples 453-456 Chiral Separation Example # method/order of elution Configuration 453 Method VI, first eluting (*S, *S) 454 Method VI, second eluting (*S, *R) 455 Method V, second eluting (*R, *S) 456 Method V, third eluting (*R, *R)

Example 454: (*S)-3-(3-(((*R)-10,10-difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (84 mg) was obtained as described in Example 453 and Table 5. MS (ESI): mass calcd. for C₃₀H₂₉F₅N₆O₄S, 664.2; m/z found, 665.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.35 (dd, J=4.7, 1.8 Hz, 1H), 8.11 (dd, J=7.8, 1.8 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.23-7.11 (m, 2H), 7.11 (dd, J=7.8, 2.0 Hz, 1H), 7.00-6.88 (m, 2H), 4.94 (dd, J=8.9, 6.8 Hz, 1H), 4.66-4.57 (m, 1H), 4.50 (d, J=14.6 Hz, 1H), 4.28-4.22 m, 1H), 4.19 (d, J=14.6 Hz, 1H), 3.78-3.63 (m, 1H), 3.29 (dd, J=13.4, 3.7 Hz, 1H), 3.24-3.10 (m, 2H), 3.05 (dd, J=16.1, 9.0 Hz, 1H), 2.80 (s, 3H), 2.28 (s, 3H), 2.08-2.00 (m, 3H), 1.62 (dt, J=9.9, 5.4 Hz, 1H), 1.29-1.19 (m, 1H).

Example 455: (*R)-3-(3-(((*S)-10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (84 mg) was obtained as described in Example 453 and Table 5. MS (ESI): mass calcd. for C₃₀H₂₉F₅N₆O₄S, 664.2; m/z found, 665.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (dd, J=4.7, 1.8 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.93 (d, J=7.1 Hz, 1H), 7.18-6.93 (m, 3H), 6.86 (dd, J=7.7, 4.7 Hz, 2H), 4.84 (t, J=7.8 Hz, 1H), 4.52 (dd, J=12.2, 4.5 Hz, 1H), 4.41 (d, J=14.7 Hz, 1H), 4.19-4.13 (m, 1H), 4.10 (d, J=14.7 Hz, 1H), 3.67-3.54 (m, 1H), 3.22 (dd, J=13.4, 3.7 Hz, 1H), 3.11 (t, J=12.8 Hz, 1H), 3.04 (dd, J=15.9, 6.7 Hz, 1H), 2.92 (dd, J=15.9, 8.9 Hz, 1H), 2.71 (s, 3H), 2.19 (s, 3H), 1.99-1.92 (m, 3H), 1.53 (dd, J=12.3, 7.6 Hz, 1H), 1.22-1.13 (m, 1H).

Example 456: (*R)-3-(3-(((*R)-10,10-Difluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (97 mg) was obtained as described in Example 453 and Table 5. MS (ESI): mass calcd. for C₃₀H₂₉F₅N₆O₄S, 664.2; m/z found, 665.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.35 (dd, J=4.7, 1.8 Hz, 1H), 8.09 (dd, J=7.8, 1.8 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.21-7.16 (m, 1H), 7.16-7.06 (m, 2H), 6.99-6.90 (m, 2H), 4.91 (t, J=7.7 Hz, 1H), 4.63 (d, J=11.7 Hz, 1H), 4.48 (d, J=14.9 Hz, 1H), 4.29-4.22 (m, 1H), 4.18 (d, J=14.9 Hz, 1H), 3.76-3.63 (m, 1H), 3.35 (dd, J=13.4, 3.7 Hz, 1H), 3.17 (t, J=12.9 Hz, 1H), 3.07 (dd, J=16.0, 6.5 Hz, 1H), 2.97 (dd, J=15.9, 8.6 Hz, 1H), 2.79 (s, 3H), 2.25 (s, 3H), 2.03 (d, J=9.1 Hz, 3H), 1.61 (d, J=10.2 Hz, 1H), 1.29-1.02 (m, 1H).

Example 457: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.45 mL, 2.28 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 550 mg, 1.36 mmol), (*R)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 14, 488 mg, 1.91 mmol), and triphenylphosphine (529 mg, 2.02 mmol) in THF (10 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (850 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₅S, 640.2; m/z found, 641.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29-8.25 (m, 1H), 8.13 (t, J=6.8 Hz, 1H), 8.05 (dt, J=7.9, 2.0 Hz, 1H), 7.76-7.42 (m, 2H), 7.33-7.03 (m, 4H), 6.94-6.71 (m, 2H), 4.97-4.91 (m, 1H), 4.59-4.53 (m, 1H), 4.49-4.35 (m, 1H), 4.27 (dd, J=14.7, 2.9 Hz, 2H), 4.16-4.01 (m, 3H), 3.79-3.67 (m, 2H), 3.67-3.50 (m, 2H), 3.17-3.10 (m, 1H), 3.03-2.93 (m, 1H), 2.81 (d, J=10.0 Hz, 3H), 2.20 (d, J=7.3 Hz, 3H), 1.15 (td, J=7.1, 0.9 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (850 mg, 1.33 mmol), 1 M aqueous NaOH solution (12 mL, 12 mmol), and THF (12 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (800 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.26 (s, 1H), 8.33-8.27 (m, 1H), 8.20 (d, J=7.2 Hz, 1H), 8.10-8.06 (m, 1H), 7.29-7.19 (m, 1H), 7.18-7.06 (m, 2H), 7.01-6.83 (m, 3H), 4.99-4.88 (m, 1H), 4.57-4.39 (m, 2H), 4.40-4.25 (m, 2H), 4.17-4.07 (m, 1H), 3.80-3.53 (m, 4H), 3.33-3.04 (m, 3H), 3.05-2.98 (m, 1H), 2.78 (s, 1H), 2.71 (s, 2H), 2.19 (d, J=2.7 Hz, 3H).

Example 458: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 457, 800 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 60% CO₂, 40% iPrOH) to afford two diastereomers. The first eluting isomer (331 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd, J=4.7, 1.8 Hz, 1H), 8.21-8.07 (m, 2H), 7.28-7.07 (m, 4H), 6.96-6.83 (m, 2H), 4.98 (t, J=7.9 Hz, 1H), 4.58 (d, J=12.6 Hz, 1H), 4.50-4.30 (m, 3H), 3.83 (d, J=10.0 Hz, 1H), 3.76 (q, J=7.1 Hz, 1H), 3.74-3.58 (m, 4H), 3.30 (dd, J=13.0, 3.9 Hz, 1H), 3.24-3.07 (m, 2H), 3.02 (dd, J=15.7, 7.9 Hz, 1H), 2.82 (s, 3H), 2.22 (s, 3H).

Example 459: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (372 mg) from the chiral separation described in Example 458 was designated (*R). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (dd, J=4.6, 1.9 Hz, 1H), 8.09-7.96 (m, 2H), 7.15-6.96 (m, 4H), 6.85-6.72 (m, 2H), 4.87 (t, J=7.9 Hz, 1H), 4.65 (s, 1H), 4.49-4.43 (m, 1H), 4.33 (d, J=14.4 Hz, 1H), 4.30-4.18 (m, 2H), 3.76-3.63 (m, 1H), 3.66-3.52 (m, 2H), 3.50 (d, J=12.5 Hz, 2H), 3.20 (dd, J=13.1, 4.0 Hz, 1H), 3.05 (qd, J=9.3, 8.8, 4.6 Hz, 2H), 2.90 (dd, J=15.6, 8.0 Hz, 1H), 2.71 (s, 3H), 2.11 (s, 3H).

Example 460: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.45 mL, 2.28 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 500 mg, 1.24 mmol), (*S)-6,7,7a,8,10,11-hexahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 13, 444 mg, 1.74 mmol), and triphenylphosphine (481 mg, 1.83 mmol) in THF (8.7 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (780 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₅S, 640.2; m/z found, 641.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.25-8.21 (m, 1H), 8.10 (t, J=6.8 Hz, 1H), 8.00 (dt, J=7.8, 2.1 Hz, 1H), 7.66-7.58 (m, 1H), 7.43-7.38 (m, 1H), 7.17-7.02 (m, 3H), 6.85-6.73 (m, 2H), 4.94-4.85 (m, 1H), 4.55-4.50 (m, 1H), 4.43-4.31 (m, 1H), 4.27-4.23 (m, 1H), 4.09-3.98 (m, 3H), 3.73-3.44 (m, 4H), 3.34-3.19 (m, 1H), 3.14-3.04 (m, 1H), 2.99-2.93 (m, 1H), 2.77 (d, J=11.0 Hz, 2H), 2.16 (d, J=8.1 Hz, 2H), 1.98 (s, 3H), 1.19 (t, J=7.1 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoate (780 mg, 1.22 mmol), 1 M aqueous NaOH solution (11 mL, 11 mmol), and THF (11 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (720 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.61 (s, 1H), 8.33-8.30 (m, 1H), 8.20 (d, J=7.2 Hz, 1H), 8.08-8.04 (m, 1H), 7.28-7.19 (m, 1H), 7.18-7.06 (m, 2H), 6.96-6.83 (m, 2H), 4.99-4.88 (m, 1H), 4.63 (dt, J=12.6, 3.6 Hz, 1H), 4.56-4.24 (m, 4H), 4.10 (dt, J=11.2, 3.5 Hz, 1H), 3.79-3.52 (m, 4H), 3.28-3.20 (m, 1H), 3.26-3.17 (m, 1H), 3.19-3.12 (m, 1H), 2.78 (s, 1H), 2.71 (s, 3H), 2.19 (d, J=2.7 Hz, 3H).

Example 461: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 460, 720 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 60% CO₂, 40% iPrOH) to afford two diastereomers. The first eluting isomer (331 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, J=4.6, 1.8 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H), 8.11 (dd, J=7.8, 1.9 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.17-7.09 (m, 1H), 7.03-6.89 (m, 3H), 4.94 (dd, J=9.8, 6.0 Hz, 1H), 4.73-4.63 (m, 1H), 4.59 (s, 2H), 4.56-4.46 (m, 2H), 4.33 (d, J=13.9 Hz, 1H), 4.18 (dt, J=11.4, 3.3 Hz, 1H), 3.84-3.66 (m, 4H), 3.32 (dd, J=13.4, 4.0 Hz, 1H), 3.27-3.21 (m, 1H), 3.13 (dd, J=14.6, 9.8 Hz, 1H), 2.98 (dd, J=14.6, 6.1 Hz, 1H), 2.75 (s, 3H), 2.22 (s, 3H).

Example 462: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-5,5-dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (386 mg) from the chiral separation described in Example 461 was designated (*R). MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₅S, 612.2; m/z found, 613.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (dd, J=4.6, 1.9 Hz, 1H), 8.12 (d, J=7.1 Hz, 1H), 8.00 (dd, J=7.8, 1.8 Hz, 1H), 7.22-7.12 (m, 2H), 7.07-6.99 (m, 1H), 6.90 (dd, J=7.8, 2.0 Hz, 1H), 6.87-6.78 (m, 2H), 4.98 (s, 1H), 4.84 (dd, J=9.5, 6.3 Hz, 1H), 4.61-4.51 (m, 1H), 4.39-4.35 (m, 2H), 4.22 (d, J=14.0 Hz, 1H), 4.09-3.90 (m, 1H), 3.72-3.55 (m, 4H), 3.21 (dd, J=13.3, 4.0 Hz, 1H), 3.16-3.11 (m, 1H), 3.04 (dd, J=14.8, 9.6 Hz, 1H), 2.89 (dd, J=14.8, 6.3 Hz, 1H), 2.64 (s, 3H), 2.11 (s, 3H).

Example 463: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.41 mL, 2.07 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 500 mg, 1.24 mmol), (R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (Intermediate 91, 397 mg, 1.74 mmol), and triphenylphosphine (529 mg, 2.02 mmol) in THF (8.7 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (730 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₃F₂N₅O₅S, 613.2; m/z found, 614.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (dt, J=4.6, 2.2 Hz, 1H), 8.25-8.20 (m, 1H), 8.14 (dd, J=7.3, 3.0 Hz, 1H), 7.58-7.37 (m, 1H), 7.31-7.22 (m, 1H), 6.83 (dd, J=7.3, 1.0 Hz, 1H), 4.96-4.91 (m, 1H), 4.43 (dt, J=14.3, 9.2 Hz, 2H), 4.15-4.01 (m, 3H), 3.58-3.52 (m, 1H), 3.16-3.10 (m, 2H), 3.00-2.95 (m, 1H), 2.80 (d, J=2.0 Hz, 3H), 2.39 (d, J=10.8 Hz, 1H), 2.29 (d, J=1.4 Hz, 3H), 2.02 (s, 1H), 1.80-1.64 (m, 1H), 1.56-1.51 (m, 1H), 1.24 (t, J=7.2 Hz, 1H), 1.15 (td, J=7.1, 2.2 Hz, 3H), 1.00 (dt, J=26.7, 7.4 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoate (750 mg, 1.22 mmol), 1 M aqueous NaOH solution (11 mL, 11 mmol), and THF (11 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (650 mg, 91%) as a white foam. MS (ESI): mass calcd. for C₂₈H₂₉F₂N₅O₅S, 585.6; m/z found, 586.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.99 (s, 1H), 8.47 (dt, J=4.9, 1.9 Hz, 1H), 8.27-8.21 (m, 1H), 8.15 (dd, J=7.1, 5.0 Hz, 1H), 7.33-7.24 (m, 1H), 7.24-7.10 (m, 3H), 7.13-7.06 (m, 1H), 6.91 (dd, J=7.3, 2.6 Hz, 1H), 4.95 (dt, J=8.8, 6.3 Hz, 1H), 4.43 (t, J=14.4 Hz, 2H), 4.07 (dd, J=14.4, 9.6 Hz, 1H), 3.59-3.51 (m, 1H), 3.23-3.14 (m, 1H), 3.17-3.10 (m, 1H), 3.09-3.02 (m, 1H), 2.75 (d, J=4.8 Hz, 3H), 2.29 (s, 3H), 1.73-1.58 (m, 1H), 1.49-1.41 (m, 1H), 1.00-0.91 (m, 2H), 0.91 (d, J=7.4 Hz, 1H).

Example 464: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 463, 650 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 55% CO₂, 45% EtOH) to afford two diastereomers. The first eluting isomer (313 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₉F₂N₅O₅S, 585.6; m/z found, 586.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.48 (s, 1H), 8.25 (dd, J=7.7, 2.0 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.29 (q, J=7.1 Hz, 2H), 7.22-7.07 (m, 3H), 6.88 (d, J=7.2 Hz, 1H), 4.95 (t, J=7.7 Hz, 1H), 4.47-4.38 (m, 2H), 4.12 (d, J=14.4 Hz, 1H), 3.73 (q, J=7.0 Hz, 1H), 3.58 (dd, J=14.9, 10.9 Hz, 1H), 3.21-3.13 (m, 2H), 3.04 (dd, J=15.8, 8.7 Hz, 1H), 2.77 (s, 3H), 2.30 (s, 3H), 1.69 (dt, J=14.7, 7.5 Hz, 1H), 1.55-1.51 (m, 1H), 0.99 (t, J=7.3 Hz, 3H).

Example 465: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (297 mg) from the chiral separation described in Example 464 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₉F₂N₅O₅S, 585.6; m/z found, 586.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.99 (s, 1H), 8.47 (dt, J=4.9, 1.9 Hz, 1H), 8.27-8.21 (m, 1H), 8.15 (dd, J=7.1, 5.0 Hz, 1H), 7.33-7.24 (m, 1H), 7.24-7.10 (m, 3H), 7.13-7.06 (m, 1H), 6.91 (dd, J=7.3, 2.6 Hz, 1H), 4.95 (dt, J=8.8, 6.3 Hz, 1H), 4.43 (t, J=14.4 Hz, 2H), 4.07 (dd, J=14.4, 9.6 Hz, 1H), 3.59-3.52 (m, 1H), 3.23-3.14 (m, 1H), 3.17-3.10 (m, 1H), 3.09-3.02 (m, 1H), 2.75 (d, J=4.8 Hz, 3H), 2.29 (s, 3H), 1.73-1.58 (m, 1H), 1.49-1.43 (m, 1H), 1.00-0.91 (m, 2H), 0.91 (d, J=7.4 Hz, 1H).

Example 466: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.33 mL, 1.66 mmol) was added to ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 400 mg, 0.99 mmol), 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7, 335 mg, 1.39 mmol), and triphenylphosphine (385 mg, 1.47 mmol) in THF (7.0 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (550 mg, 89%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₂F₂N₄O₆S, 626.2; m/z found, 627.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J=7.2 Hz, 1H), 7.82 (dt, J=7.8, 1.9 Hz, 1H), 7.54 (td, J=7.7, 1.7 Hz, 1H), 7.40-7.23 (m, 3H), 7.19-7.05 (m, 4H), 6.82 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.9 Hz, 1H), 4.57 (dd, J=10.6, 7.6 Hz, 2H), 4.30-4.21 (m, 3H), 4.13-3.99 (m, 2H), 3.76-3.63 (m, 2H), 3.12 (dd, J=15.8, 7.1 Hz, 1H), 3.00 (dd, J=15.8, 8.6 Hz, 1H), 2.79 (s, 3H), 2.24 (s, 3H), 1.14 (td, J=7.1, 1.7 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoate (550 mg, 0.88 mmol), 1 M aqueous NaOH solution (8.1 mL, 8.1 mmol), and THF (8.1 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (500 mg, 95%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₈F₂N₄O₆S, 598.2; m/z found, 599.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (s, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.77 (dd, J=7.8, 1.7 Hz, 1H), 7.59-7.42 (m, 3H), 7.35 (td, J=7.6, 3.0 Hz, 1H), 7.25-7.18 (m, 1H), 7.15-6.98 (m, 1H), 6.83 (d, J=7.3 Hz, 1H), 4.83 (t, J=7.9 Hz, 1H), 4.54 (dd, J=9.5, 7.6 Hz, 2H), 4.33 (d, J=14.4 Hz, 1H), 4.24-4.14 (m, 3H), 4.04 (q, J=7.1 Hz, 1H), 3.70 (d, J=15.2 Hz, 1H), 3.61 (d, J=15.2 Hz, 1H), 3.05 (dd, J=15.3, 8.4 Hz, 1H), 2.93 (dd, J=15.2, 7.4 Hz, 1H), 2.63 (s, 3H), 2.18 (s, 3H).

Example 467: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 466, 500 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 55% CO₂, 45% EtOH) to afford two enantiomers. The first eluting isomer (199 mg) was further purified by preparative LC (Stationary phase: irregular bare silica 24 g, Mobile phase: Gradient from 90% DCM, 10% MeOH to 85% DCM, 15% MeOH) to afford the isomer (172 mg) which was designated (*S). MS (ESI): mass calcd. for C₂₉H₂₈F₂N₄O₆S, 598.2; m/z found, 599.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=7.2 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.39-7.26 (m, 3H), 7.21 (d, J=9.1 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.88 (d, J=7.1 Hz, 1H), 4.86 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 4.42 (d, J=14.6 Hz, 1H), 4.27 (d, J=13.4 Hz, 3H), 3.80 (d, J=15.4 Hz, 1H), 3.76-3.68 (m, 1H), 3.06 (s, 1H), 2.93 (s, 1H), 2.69 (s, 3H), 2.25 (s, 3H).

Example 468: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (209 mg) from the chiral separation described in Example 467 was designated (*R). MS (ESI): mass calcd. for C₂₉H₂₈F₂N₄O₆S, 598.6; m/z found, 599.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J=7.2 Hz, 1H), 7.88 (dd, J=7.8, 1.7 Hz, 1H), 7.58 (td, J=7.8, 1.7 Hz, 1H), 7.38 (dd, J=8.1, 1.1 Hz, 1H), 7.33 (dd, J=7.6, 1.2 Hz, 1H), 7.33-7.07 (m, 3H), 7.04 (dd, J=7.9, 1.9 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.90 (t, J=8.0 Hz, 1H), 4.67 (t, J=8.0 Hz, 2H), 4.48 (d, J=14.3 Hz, 1H), 4.34-4.23 (m, 3H), 3.82 (d, J=15.3 Hz, 1H), 3.76-3.69 (m, 1H), 3.12 (dd, J=14.9, 9.1 Hz, 1H), 3.01 (dd, J=14.9, 6.8 Hz, 1H), 2.72 (s, 3H), 2.28 (s, 3H).

Example 469: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.33 mL, 1.66 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 400 mg, 0.99 mmol), 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59, 337 mg, 1.39 mmol), and triphenylphosphine (385 mg, 1.47 mmol) in THF (7.0 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (540 mg, 87%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₁F₂N₅O₆S, 627.2; m/z found, 628.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47 (dd, J=4.8, 1.9 Hz, 1H), 8.14 (dd, J=7.6, 1.9 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.63-7.53 (m, 2H), 7.50-7.32 (m, 3H), 7.30-7.18 (m, 1H), 7.14-6.98 (m, 4H), 6.76 (d, J=7.2 Hz, 1H), 4.87 (t, J=7.9 Hz, 1H), 4.64 (dd, J=7.6, 6.2 Hz, 2H), 4.37-4.23 (m, 2H), 3.77-3.63 (m, 1H), 3.06 (dd, J=15.8, 7.2 Hz, 1H), 2.94 (dd, J=15.8, 8.6 Hz, 1H), 2.74 (s, 3H), 2.18 (s, 3H), 1.09 (t, J=7.1 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate (540 mg, 0.86 mmol), 1 M aqueous NaOH solution (8 mL, 8 mmol), and THF (8 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (480 mg, 93%) as a white foam. MS (ESI): mass calcd. for C₂₄H₂₇F₂N₅O₆S, 599.2; m/z found, 600.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.58 (s, 1H), 8.52 (dd, J=4.9, 1.9 Hz, 1H), 8.21 (dd, J=7.7, 1.9 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.36-7.29 (m, 1H), 7.22-7.02 (m, 4H), 6.92 (d, J=7.3 Hz, 1H), 4.93 (t, J=7.9 Hz, 1H), 4.67 (t, J=7.7 Hz, 2H), 4.43 (d, J=14.5 Hz, 1H), 4.36-4.25 (m, 3H), 3.84 (d, J=15.1 Hz, 1H), 3.75 (d, J=15.1 Hz, 1H), 3.15 (dd, J=15.5, 8.1 Hz, 1H), 3.03 (dd, J=15.5, 7.7 Hz, 1H), 2.71 (s, 3H), 2.24 (s, 3H).

Example 470: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 469, 480 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 55% CO₂, 45% EtOH) to afford two enantiomers. The first eluting isomer (223 mg) was further purified by preparative LC (Stationary phase: irregular bare silica 24 g, Mobile phase: Gradient from 90% DCM, 10% MeOH to 85% DCM, 15% MeOH) to afford the isomer (213 mg) which was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₇F₂N₅O₆S, 599.2; m/z found, 600.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.45 (dd, J=5.1, 1.9 Hz, 1H), 8.14 (dd, J=7.7, 2.0 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.29-7.16 (m, 1H), 7.13 (d, J=10.7 Hz, 1H), 7.03 (t, J=8.3 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.81 (d, J=7.2 Hz, 1H), 5.22 (s, 1H), 4.82 (t, J=8.0 Hz, 1H), 4.61 (t, J=6.8 Hz, 2H), 4.35 (d, J=14.6 Hz, 1H), 4.30-4.23 (m, 3H), 3.77 (d, J=15.3 Hz, 1H), 3.70 (d, J=15.2 Hz, 1H), 3.00 (s, 1H), 2.88 (s, 1H), 2.62 (s, 3H), 2.16 (s, 3H).

Example 471: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (202 mg) from the chiral separation described in Example 470 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₇F₂N₅O₆S, 599.2; m/z found, 600.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.56 (dd, J=5.0, 1.9 Hz, 1H), 8.25 (dd, J=7.7, 1.9 Hz, 1H), 8.19 (d, J=7.2 Hz, 1H), 7.39-7.31 (m, 1H), 7.23 (s, 1H), 7.21-7.10 (m, 1H), 7.05 (dd, J=7.8, 1.9 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.95-4.87 (m, 1H), 4.76 (dd, J=10.3, 7.7 Hz, 2H), 4.52 (d, J=14.2 Hz, 1H), 4.41-4.31 (m, 3H), 3.89 (d, J=15.3 Hz, 1H), 3.83-3.68 (m, 2H), 3.13 (dd, J=15.0, 9.2 Hz, 1H), 3.01 (dd, J=15.0, 6.7 Hz, 1H), 2.73 (s, 3H), 2.27 (s, 3H).

Example 472: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.33 mL, 1.66 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 400 mg, 0.99 mmol), 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 5, 224 mg, 0.99 mmol), and triphenylphosphine (414 mg, 1.58 mmol) in THF (13 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (550 mg, 91%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₁F₂N₅O₅S, 611.2; m/z found, 612.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (dd, J=4.8, 2.0 Hz, 1H), 8.26 (dd, J=7.7, 2.0 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.71-7.60 (m, 1H), 7.58-7.40 (m, 1H), 7.36-7.27 (m, 1H), 7.16-7.04 (m, 3H), 6.83 (d, J=7.2 Hz, 1H), 4.91 (t, J=7.8 Hz, 1H), 4.30 (s, 1H), 4.07 (dq, J=16.2, 7.1 Hz, 2H), 3.52 (s, 2H), 3.12 (dd, J=15.9, 7.3 Hz, 1H), 3.00 (dd, J=15.9, 8.5 Hz, 1H), 2.78 (s, 3H), 2.28 (s, 3H), 1.23-1.17 (m, 5H), 0.60-0.48 (m, 2H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate (550 mg, 0.90 mmol), 1 M aqueous NaOH solution (8.3 mL, 8.3 mmol), THF (8.3 mL) and ethanol (0.05 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (520 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₂₄H₂₇F₂N₅O₅S, 583.3; m/z found, 584.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.18 (s, 1H), 8.44 (dd, J=4.9, 1.9 Hz, 1H), 8.30 (dd, J=7.6, 1.9 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.37-7.30 (m, 1H), 7.16-7.08 (m, 2H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 6.88 (d, J=7.3 Hz, 1H), 5.30 (s, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.37-4.26 (m, 2H), 3.49 (d, J=18.5 Hz, 2H), 3.17 (dd, J=15.9, 7.1 Hz, 1H), 3.04 (dd, J=15.9, 8.5 Hz, 1H), 2.76 (s, 3H), 2.29 (s, 3H), 1.06 (s, 2H), 0.53-0.43 (m, 2H).

Example 473: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 472, 520 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 55% CO₂, 45% EtOH) to afford two enantiomers. The first eluting isomer (254 mg) was further purified by preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: Gradient from 90% DCM, 10% MeOH to 80% DCM, 20% MeOH) to afford the isomer (235 mg) which was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₇F₂N₅O₅S, 583.3; m/z found, 584.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.45 (dd, J=5.1, 1.9 Hz, 1H), 8.14 (dd, J=7.7, 2.0 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.29-7.16 (m, 1H), 7.13 (d, J=10.7 Hz, 1H), 7.03 (t, J=8.3 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.81 (d, J=7.2 Hz, 1H), 5.22 (s, 1H), 4.82 (t, J=8.0 Hz, 1H), 4.61 (t, J=6.8 Hz, 2H), 4.35 (d, J=14.6 Hz, 1H), 4.30-4.23 (m, 3H), 3.77 (d, J=15.3 Hz, 1H), 3.70 (d, J=15.2 Hz, 1H), 3.00 (s, 1H), 2.88 (s, 1H), 2.62 (s, 3H), 2.16 (s, 3H).

Example 474: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (202 mg) from the chiral separation described in Example 473 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₇F₂N₅O₅S, 583.3; m/z found, 584.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.45 (dd, J=4.9, 1.9 Hz, 1H), 8.30 (dd, J=7.6, 1.9 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.37-7.30 (m, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.06 (d, J=7.5 Hz, 1H), 6.84 (d, J=7.3 Hz, 1H), 5.31 (s, 1H), 4.94 (t, J=7.8 Hz, 1H), 4.36 (d, J=14.5 Hz, 1H), 4.28 (d, J=14.6 Hz, 1H), 3.59 (d, J=15.5 Hz, 1H), 3.47 (d, J=12.3 Hz, 1H), 3.13 (dd, J=15.9, 7.0 Hz, 1H), 2.99 (dd, J=15.8, 8.5 Hz, 1H), 2.77 (s, 3H), 2.29 (s, 3H), 1.24 (t, J=7.0 Hz, 1H), 1.09-1.02 (m, 2H), 0.57-0.50 (m, 2H).

Example 475: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoate. DBAD (347 mg, 1.51 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 400 mg, 0.99 mmol), (*S)-7a-methyl-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 39, 326 mg, 1.29 mmol), and triphenylphosphine (403 mg, 1.54 mmol) in THF (12 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (500 mg, 79%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₆F₂N₆O₄S, 638.9; m/z found, 638.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.41-8.32 (m, 1H), 8.12 (dd, J=7.7, 1.9 Hz, 1H), 7.44 (d, J=3.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.23 (d, J=1.8 Hz, 1H), 7.15-7.03 (m, 2H), 6.95-6.85 (m, 3H), 4.26 (dd, J=21.6, 15.5 Hz, 1H), 4.16-4.02 (m, 4H), 3.06 (d, J=8.9 Hz, 1H), 2.90-2.77 (m, 4H), 2.24 (d, J=10.2 Hz, 4H), 2.02 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.14 (td, J=7.1, 2.5 Hz, 3H), 0.84 (d, J=6.0 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoate (500 mg, 0.78 mmol), 1 M aqueous NaOH solution (7.2 mL, 7.2 mmol), THF (7.2 mL) and ethanol (0.05 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (440 mg, 92%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₄S, 610.2; m/z found, 611.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 8.16 (dd, J=13.6, 7.4 Hz, 2H), 7.29 (d, J=14.8 Hz, 2H), 7.15-7.02 (m, 3H), 6.92 (dt, J=13.4, 7.2 Hz, 2H), 5.85 (s, 1H), 4.96 (d, J=8.2 Hz, 1H), 4.78 (t, J=15.8 Hz, 1H), 4.30-4.22 (m, 1H), 3.93 (d, J=10.1 Hz, 1H), 3.57 (s, 1H), 3.21-3.10 (m, 1H), 3.04 (s, 1H), 2.84-2.80 (m, 3H), 2.26 (d, J=11.6 Hz, 3H), 1.88 (d, J=19.7 Hz, 3H), 1.79 (d, J=6.3 Hz, 1H), 0.86 (d, J=6.9 Hz, 3H).

Example 476: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid isomers (Example 475, 440 mg) was separated by chiral SFC (stationary phase: Chiralpak IA 5 μm 250×20 mm, isocratic mobile phase: 60% CO₂, 40% EtOH) to afford two diastereomers. The first eluting isomer (195 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₄S, 610.2; m/z found, 611.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (dd, J=4.8, 1.8 Hz, 1H), 8.11-7.99 (m, 2H), 7.31-7.17 (m, 2H), 7.18-7.02 (m, 1H), 7.05-6.91 (m, 2H), 6.90-6.76 (m, 2H), 5.85 (s, 1H), 4.90 (dd, J=8.9, 6.8 Hz, 1H), 4.68 (d, J=15.8 Hz, 1H), 4.21 (d, J=15.8 Hz, 1H), 3.89-3.82 (m, 1H), 3.71 (d, J=14.7 Hz, 1H), 3.49-3.45 (m, 1H), 3.14 (dd, J=16.0, 6.8 Hz, 1H), 3.00 (dd, J=16.0, 8.9 Hz, 1H), 2.72 (s, 3H), 2.18 (s, 3H), 1.84-1.68 (m, 4H), 0.78 (s, 3H).

Example 477: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-7a-methyl-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (202 mg) from the chiral separation described in Example 476 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₄S, 610.2; m/z found, 611.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (dd, J=4.8, 1.9 Hz, 1H), 8.23-8.11 (m, 2H), 7.26 (d, J=1.9 Hz, 1H), 7.20-7.06 (m, 3H), 7.00-6.86 (m, 2H), 6.48 (s, 1H), 5.31 (s, 1H), 5.01-4.94 (m, 1H), 4.80 (d, J=15.3 Hz, 1H), 4.27 (d, J=15.3 Hz, 1H), 3.95-3.85 (m, 1H), 3.66 (d, J=14.7 Hz, 1H), 3.57-3.48 (m, 1H), 3.20 (dd, J=16.1, 6.8 Hz, 1H), 3.09 (dd, J=16.1, 8.9 Hz, 1H), 2.79 (s, 3H), 2.28 (s, 3H), 1.80 (dt, J=8.0, 5.1 Hz, 2H), 1.80-1.69 (m, 1H), 1.69-1.63 (m, 1H), 0.83 (s, 3H).

Example 478: 3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.15 mL, 0.78 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 200 mg, 0.47 mmol), (*S)-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 2, 170 mg, 0.67 mmol), and triphenylphosphine (184 mg, 0.70 mmol) in THF (5 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (311 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₄F₃N₇O₄S, 657.8; m/z found, 657.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.25 (dd, J=4.7, 1.8 Hz, 1H), 8.03-7.93 (m, 2H), 7.39-7.33 (m, 1H), 7.30-7.22 (m, 1H), 6.78 (dd, J=7.8, 4.7 Hz, 1H), 5.00 (q, J=7.7 Hz, 1H), 4.71-4.56 (m, 2H), 4.38-4.22 (m, 2H), 4.11-3.95 (m, 2H), 3.59-3.31 (m, 4H), 3.07-3.00 (m, 1H), 2.88-2.84 (m, 3H), 2.29-2.21 (m, 1H), 1.99 (s, 2H), 1.81-1.60 (m, 4H), 1.57-1.50 (m, 2H), 1.39 (tt, J=10.5, 4.7 Hz, 1H), 1.12 (t, J=7.1 Hz, 3H).

Step B: 3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (311 mg, 0.47 mmol), 1 M aqueous NaOH solution (4.4 mL, 4.4 mmol), THF (4.4 mL) and ethanol (0.03 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (296 mg, 99%) as a white foam. This foam was further purified via preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 94% DCM, 6% MeOH) to provide the title compound as a white foam (286 mg). MS (ESI): mass calcd. for C₂₉H₃₀F₃N₇O₄S, 629.2; m/z found, 629.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.33-8.30 (m, 1H), 8.09-8.03 (m, 1H), 7.99 (dd, J=14.1, 7.2 Hz, 1H), 7.47-7.38 (m, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.10-7.00 (m, 1H), 6.86-6.82 (m, 1H), 5.08-4.99 (m, 1H), 4.73 (dd, J=14.6, 2.7 Hz, 1H), 4.66 (tt, J=11.4, 5.8 Hz, 1H), 4.39-4.26 (m, 2H), 3.64-3.35 (m, 5H), 3.09-3.05 (m, 1H), 2.87 (d, J=3.7 Hz, 3H), 2.34 (s, 1H), 2.28 (s, 2H), 1.78 (s, 2H), 1.83-1.68 (m, 1H), 1.21 (t, J=7.0 Hz, 3H).

Example 479: (*S)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 478, 286 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two diastereomers. The first eluting diastereomer (124 mg) was further purified using preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the diastereomer (117 mg) which was designated (*S). MS (ESI): mass calcd. for C₂₉H₃₀F₃N₇O₄S, 629.2; m/z found, 629.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (dd, J=4.6, 1.9 Hz, 1H), 8.06 (dd, J=7.8, 1.9 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.43-7.38 (m, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.84 (dd, J=7.8, 4.6 Hz, 1H), 5.04 (t, J=7.4 Hz, 1H), 4.73 (d, J=15.2 Hz, 1H), 4.64 (dt, J=10.3, 5.1 Hz, 1H), 4.35 (dd, J=14.3, 4.2 Hz, 2H), 3.73 (q, J=7.0 Hz, 1H), 3.63-3.48 (m, 3H), 3.45-3.35 (m, 1H), 3.01 (dd, J=16.4, 6.7 Hz, 1H), 2.88 (s, 3H), 2.29 (s, 3H), 1.83-1.72 (m, 1H), 1.63 (dd, J=13.7, 6.5 Hz, 1H), 1.59-1.53 (m, 1H), 1.33-1.21 (m, 3H).

Example 480: (*R)-3-(6-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting diastereomer (130 mg) from the chiral separation described in Example 479 was designated (*R). MS (ESI): mass calcd. for C₂₉H₃₀F₃N₇O₄S, 629.2; m/z found, 629.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (dd, J=4.7, 1.8 Hz, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.47-7.38 (m, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.85 (dd, J=7.8, 4.7 Hz, 1H), 5.02 (t, J=7.3 Hz, 1H), 4.73 (d, J=14.1 Hz, 1H), 4.63 (dq, J=14.3, 4.5 Hz, 1H), 4.39-4.23 (m, 2H), 3.74 (q, J=7.1 Hz, 1H), 3.54 (t, J=12.9 Hz, 1H), 3.53-3.40 (m, 2H), 3.29 (dd, J=13.4, 3.7 Hz, 1H), 3.10 (dd, J=16.4, 7.2 Hz, 1H), 2.88 (s, 3H), 2.35 (s, 3H), 1.79 (d, J=5.8 Hz, 1H), 1.77-1.67 (m, 1H), 1.62-1.40 (m, 3H), 1.25 (t, J=7.0 Hz, 1H).

Example 481: (R/S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DBAD (149 mg, 0.65 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 180 mg, 0.43 mmol), 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 5, 96.4 mg, 0.43 mmol), and triphenylphosphine (177 mg, 0.68 mmol) in THF (5.8 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (250 mg, 93%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₅S, 630.2; m/z found, 630.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.42 (dd, J=4.9, 1.9 Hz, 1H), 8.25 (dd, J=7.6, 1.9 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.6, 4.9 Hz, 1H), 7.10-7.00 (m, 2H), 4.92 (t, J=7.6 Hz, 1H), 4.47 (d, J=13.4 Hz, 1H), 4.35 (d, J=13.4 Hz, 1H), 4.09-3.92 (m, 2H), 3.71 (d, J=15.1 Hz, 1H), 3.43 (d, J=15.4 Hz, 1H), 3.27 (dd, J=16.1, 8.2 Hz, 1H), 2.91-2.73 (m, 4H), 2.36 (s, 3H), 1.18-1.10 (m, 5H), 0.94-0.86 (m, 1H), 0.80-0.70 (m, 1H).

Step B: 3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (250 mg, 0.40 mmol), 1 M aqueous NaOH solution (3.7 mL, 3.7 mmol), THF (3.7 mL) and ethanol (0.02 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (230 mg, 96%) as a white foam. This foam was further purified via preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 95% DCM, 5% MeOH) to provide the title compound as a white foam (220 mg, 92%). MS (ESI): mass calcd. for C₂₇H₂₅F₃N₆O₅S, 602.2; m/z found, 602.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.45 (dd, J=4.9, 2.0 Hz, 1H), 8.31 (dd, J=7.6, 1.9 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.35 (dd, J=7.6, 4.9 Hz, 1H), 7.08 (dd, J=7.6, 4.7 Hz, 2H), 4.98 (t, J=7.5 Hz, 1H), 4.54 (d, J=13.5 Hz, 1H), 4.38 (d, J=13.5 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.80 (d, J=14.9 Hz, 1H), 3.38 (dd, J=16.4, 8.0 Hz, 1H), 2.95 (dd, J=16.4, 7.0 Hz, 1H), 2.81 (s, 3H), 2.39 (s, 3H), 1.18 (dt, J=11.8, 6.1 Hz, 1H), 1.09 (dt, J=11.4, 6.1 Hz, 1H), 0.75 (dt, J=10.4, 6.5 Hz, 2H).

Example 482: (*S)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 481, 220 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 65% CO₂, 35% MeOH) to afford two enantiomers. The first eluting enantiomer (100 mg) was designated (*S). MS (ESI): mass calcd. for C₂₇H₂₅F₃N₆O₅S, 602.2; m/z found, 602.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (dd, J=4.9, 1.9 Hz, 1H), 8.23 (dd, J=7.6, 2.0 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.26 (dd, J=7.6, 4.9 Hz, 1H), 7.19 (s, 1H), 7.00 (dd, J=11.9, 7.5 Hz, 2H), 4.87 (t, J=7.5 Hz, 1H), 4.46 (d, J=13.6 Hz, 1H), 4.30 (d, J=13.6 Hz, 1H), 3.72 (d, J=15.7 Hz, 1H), 3.43 (d, J=15.6 Hz, 1H), 3.15 (dd, J=16.0, 7.6 Hz, 1H), 2.82-2.73 (m, 1H), 2.73 (s, 3H), 2.31 (s, 3H), 0.94-0.83 (m, 2H), 0.84 (d, J=6.7 Hz, 1H), 0.72-0.63 (m, 1H).

Example 483: (*R)-3-(6-((1′,1′-Dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (100 mg) from the chiral separation described in Example 482 was designated (*R). MS (ESI): mass calcd. for C₂₇H₂₅F₃N₆O₅S, 602.2; m/z found, 602.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (dd, J=4.9, 1.9 Hz, 1H), 8.23 (dd, J=7.6, 2.0 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.37-7.27 (m, 1H), 7.25 (dd, J=7.6, 4.9 Hz, 1H), 7.19 (s, 1H), 7.01 (t, J=8.1 Hz, 2H), 4.87 (t, J=7.6 Hz, 1H), 4.44 (d, J=13.6 Hz, 1H), 4.29 (d, J=13.6 Hz, 1H), 3.71 (d, J=15.7 Hz, 1H), 3.43 (d, J=15.7 Hz, 1H), 3.10 (dd, J=15.9, 7.5 Hz, 1H), 2.79-2.72 (m, 1H), 2.73 (s, 3H), 2.31 (s, 3H), 0.97-0.79 (m, 3H), 0.72-0.64 (m, 1H).

Example 484: 3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.17 mL, 0.88 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 220 mg, 0.52 mmol), 2,3-dihydrospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetane] 1,1-dioxide (Intermediate 7, 0.74 mmol), and triphenylphosphine (203 mg, 0.77 mmol) in THF (6 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (310 mg, 92%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₆S, 645.2; m/z found, 645.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J=7.2 Hz, 1H), 7.83 (dt, J=7.9, 1.8 Hz, 1H), 7.64-7.37 (m, 4H), 7.33-7.21 (m, 1H), 7.22-7.10 (m, 2H), 4.99 (t, J=7.6 Hz, 1H), 4.69 (dd, J=7.2, 2.8 Hz, 2H), 4.65-4.55 (m, 1H), 4.52 (d, J=7.4 Hz, 1H), 4.42-4.34 (m, 1H), 4.26 (d, J=14.0 Hz, 1H), 4.11-3.88 (m, 3H), 3.72 (d, J=15.3 Hz, 1H), 3.41 (dd, J=16.2, 8.0 Hz, 1H), 2.97 (dd, J=16.2, 7.2 Hz, 1H), 2.84 (s, 2H), 2.35 (s, 3H), 1.10 (td, J=7.1, 1.4 Hz, 3H).

Step B: 3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (310 mg, 0.48 mmol), 1 M aqueous NaOH solution (4.4 mL, 4.4 mmol), THF (4.4 mL) and ethanol (0.03 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (292 mg, 98%) as a white foam. This foam was further purified by preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound (284 mg, 96%). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.2; m/z found, 617.8 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 8.00 (d, J=7.1 Hz, 1H), 7.86 (dd, J=7.8, 1.7 Hz, 1H), 7.60 (td, J=7.7, 1.7 Hz, 1H), 7.50-7.39 (m, 2H), 7.16 (d, J=7.3 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 5.30 (s, 1H), 5.04 (dd, J=8.8, 6.3 Hz, 1H), 4.72 (dd, J=7.5, 4.2 Hz, 2H), 4.63 (t, J=7.7 Hz, 2H), 4.46 (d, J=13.9 Hz, 1H), 4.35 (d, J=14.0 Hz, 1H), 3.98 (d, J=15.2 Hz, 1H), 3.79 (d, J=15.4 Hz, 1H), 3.52-3.41 (m, 1H), 2.98 (dd, J=16.3, 6.3 Hz, 1H), 2.81 (s, 3H), 2.39 (s, 3H).

Example 485: (*S)-3-(6-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-((1,1-Dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 484, 292 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 65% CO₂, 35% MeOH) to afford two enantiomers. The first eluting enantiomer (100 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.2; m/z found, 617.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=7.1 Hz, 1H), 7.81 (dd, J=7.8, 1.7 Hz, 1H), 7.52 (td, J=7.8, 1.7 Hz, 1H), 7.43-7.27 (m, 2H), 6.94 (dd, J=9.1, 7.6 Hz, 2H), 5.23 (s, 1H), 4.94 (dd, J=9.2, 5.9 Hz, 1H), 4.64 (dd, J=7.5, 2.1 Hz, 2H), 4.63-4.41 (m, 3H), 4.21 (d, J=13.9 Hz, 1H), 3.87 (d, J=15.4 Hz, 1H), 3.74 (d, J=15.4 Hz, 1H), 3.25 (dd, J=16.0, 9.3 Hz, 1H), 2.84-2.74 (m, 1H), 2.74 (s, 3H), 2.32 (s, 3H).

Example 486: (*R)-3-(6-((1,1-dioxidospiro[benzo[b][1,4,5]oxathiazepine-4,3′-oxetan]-2(3H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (100 mg) from the chiral separation described in Example 485 was designated (*R). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₆S, 617.2; m/z found, 617.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J=7.1 Hz, 1H), 7.80 (dd, J=7.8, 1.7 Hz, 1H), 7.52 (td, J=7.8, 1.7 Hz, 1H), 7.35 (t, J=7.4 Hz, 2H), 7.03-6.88 (m, 2H), 5.23 (s, 1H), 4.94 (dd, J=9.0, 6.0 Hz, 1H), 4.63 (d, J=7.5 Hz, 2H), 4.56 (d, J=7.5 Hz, 1H), 4.52-4.39 (m, 2H), 4.21 (d, J=13.9 Hz, 1H), 3.87 (d, J=15.4 Hz, 1H), 3.73 (d, J=15.4 Hz, 1H), 3.24 (dd, J=15.9, 9.0 Hz, 1H), 2.82-2.75 (m, 1H), 2.74 (s, 3H), 2.32 (s, 3H).

Example 487: 3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Ethyl 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoate. Diisopropyl azodicarboxylate (0.08 mL, 0.39 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 100 mg, 0.24 mmol), (*S)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 77, 90 mg, 0.34 mmol), and triphenylphosphine (92 mg, 0.35 mmol) in THF (3 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (150 mg, 94%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₆F₃N₇O₄S, 671.9; m/z found, 671.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (dd, J=2.2, 1.0 Hz, 1H), 7.99 (dd, J=11.2, 7.2 Hz, 1H), 7.89-7.85 (m, 1H), 7.42 (dd, J=12.8, 7.8 Hz, 1H), 7.27 (dd, J=10.5, 7.3 Hz, 1H), 7.13-7.07 (m, 1H), 5.04 (td, J=7.5, 5.7 Hz, 1H), 4.75-4.54 (m, 2H), 4.39-4.26 (m, 2H), 4.18-3.98 (m, 1H), 3.63-3.35 (m, 4H), 3.14-2.88 (m, 4H), 2.35 (s, 1H), 2.29 (d, J=3.1 Hz, 2H), 2.05 (s, 1H), 1.87-1.36 (m, 7H), 1.35-1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H).

Step B: 3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid. A mixture containing ethyl 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoate (150 mg, 0.22 mmol), 1 M aqueous NaOH solution (2 mL, 2 mmol), THF (2 mL) and ethanol (0.01 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (136 mg, 95%) as a white foam. This foam was further purified via preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound as a white foam (126 mg, 88%). MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 643.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21-8.09 (m, 1H), 7.98 (dd, J=16.1, 7.2 Hz, 1H), 7.89-7.84 (m, 1H), 7.66-7.60 (m, 1H), 7.48-7.37 (m, 1H), 7.07 (dd, J=25.8, 7.8 Hz, 1H), 5.03 (q, J=7.1 Hz, 1H), 4.73-4.66 (m, 1H), 4.56 (dt, J=12.4, 7.1 Hz, 1H), 4.36 (d, J=15.1 Hz, 1H), 4.33-4.19 (m, 1H), 3.60-3.49 (m, 1H), 3.51-3.42 (m, 2H), 3.46-3.33 (m, 1H), 3.09-3.04 (m, 1H), 2.87 (d, J=2.3 Hz, 3H), 2.35 (s, 3H), 2.34-2.21 (m, 3H), 1.78-1.70 (m, 3H), 1.66 (d, J=13.9 Hz, 1H), 1.20 (t, J=7.0 Hz, 2H).

Example 488: (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid isomers (Example 487, 126 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 30% CO₂, 70% MeOH) to afford two diasteromers. The first eluting diastereomer (44 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 643.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J=2.3 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.48-7.35 (m, 1H), 7.27-7.14 (m, 1H), 7.03 (d, J=7.8 Hz, 1H), 5.05 (t, J=7.4 Hz, 1H), 4.71 (d, J=15.1 Hz, 1H), 4.63-4.51 (m, 1H), 4.37 (d, J=15.1 Hz, 1H), 4.26 (dt, J=13.2, 4.7 Hz, 1H), 3.68-3.55 (m, 2H), 3.51 (dd, J=13.2, 3.9 Hz, 1H), 3.44-3.38 (m, 1H), 3.07-2.92 (m, 1H), 2.90 (s, 3H), 2.37-2.23 (m, 6H), 1.79-1.72 (m, 3H), 1.67-1.59 (m, 1H), 1.33-1.21 (m, 2H).

Example 489: (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting diastereomer (47 mg) from the chiral separation described in Example 488 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 643.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J=2.3 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.88 (dd, J=2.3, 0.8 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.28 (s, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 5.03 (t, J=7.3 Hz, 1H), 4.71 (d, J=14.0 Hz, 1H), 4.56 (dd, J=12.3, 4.8 Hz, 1H), 4.32 (d, J=14.0 Hz, 1H), 4.26 (dt, J=13.2, 4.8 Hz, 1H), 3.59-3.50 (m, 1H), 3.49-3.43 (m, 2H), 3.26 (dd, J=13.4, 3.7 Hz, 1H), 3.10 (dd, J=16.5, 7.2 Hz, 1H), 2.89 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.79-1.65 (m, 3H), 1.54 (q, J=6.7 Hz, 1H), 1.33-1.21 (m, 2H).

Example 490: 3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Ethyl 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoate. Diisopropyl azodicarboxylate (0.09 mL, 0.47 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 120 mg, 0.28 mmol), (*R)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 117 108 mg, 0.40 mmol), and triphenylphosphine (111 mg, 0.42 mmol) in THF (3 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (180 mg, 94%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₆F₃N₇O₄S, 671.7; m/z found, 671.9 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (dt, J=2.0, 0.9 Hz, 1H), 7.99 (dd, J=11.0, 7.2 Hz, 1H), 7.90-7.84 (m, 1H), 7.42 (dd, J=12.8, 7.8 Hz, 1H), 7.27 (dd, J=10.9, 7.3 Hz, 1H), 7.11-7.07 (m, 1H), 5.03 (td, J=7.5, 5.7 Hz, 1H), 4.75-4.53 (m, 1H), 4.38-4.25 (m, 2H), 4.17-3.97 (m, 2H), 3.62-3.34 (m, 4H), 3.22 (dd, J=13.5, 3.8 Hz, 1H), 3.14-2.88 (m, 4H), 2.34 (s, 3H), 2.28 (d, J=3.1 Hz, 3H), 1.88-1.36 (m, 6H), 1.36-1.12 (m, 3H).

Step B: 3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid. A mixture containing ethyl 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoate (180 mg, 0.27 mmol), 1 M aqueous NaOH solution (2.5 mL, 2.5 mmol), THF (2.5 mL) and ethanol (0.02 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (162 mg, 94%) as a white foam. This foam was further purified by preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound as a white foam (152 mg, 88%). MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 643.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (t, J=2.7 Hz, 1H), 7.99 (dd, J=15.1, 7.2 Hz, 1H), 7.88 (dd, J=6.3, 2.2 Hz, 1H), 7.62 (s, 1H), 7.42 (dd, J=18.2, 7.8 Hz, 1H), 7.29 (d, J=6.4 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 5.03 (q, J=7.2 Hz, 1H), 4.73-4.66 (m, 1H), 4.57 (s, 1H), 4.26-4.22 (m, 1H), 3.60-3.49 (m, 2H), 3.49 (s, 1H), 3.51-3.40 (m, 2H), 3.08-3.04 (m, 1H), 2.87 (d, J=2.2 Hz, 3H), 2.34 (s, 1H), 2.34-2.22 (m, 4H), 1.43 (s, 2H), 1.20 (t, J=7.0 Hz, 4H).

Example 491: (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of 3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid isomers (Example 490, 152 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 30% CO₂, 70% MeOH) to afford two diasteromers. The first eluting diastereomer (55 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 643.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J=2.2 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.28 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 5.31 (s, 1H), 5.03 (t, J=7.4 Hz, 1H), 4.71 (d, J=14.0 Hz, 1H), 4.60-4.52 (m, 1H), 4.32 (d, J=13.9 Hz, 1H), 4.25 (dd, J=13.3, 4.8 Hz, 1H), 3.60-3.46 (m, 2H), 3.49-3.42 (m, 1H), 3.26 (dd, J=13.5, 3.7 Hz, 1H), 3.10 (dd, J=16.4, 7.2 Hz, 1H), 2.88 (s, 3H), 2.42-2.23 (m, 5H), 1.80-1.66 (m, 1H), 1.55 (dt, J=12.7, 6.9 Hz, 1H), 1.45 (s, 2H), 1.26 (d, J=9.0 Hz, 2H).

Example 492: (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting diastereomer (58 mg) from the chiral separation described in Example 491 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₄S, 643.2; m/z found, 643.9 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.08 (d, J=2.2 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.80 (d, J=2.2 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.09 (d, J=7.3 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 5.23 (s, 1H), 4.95 (t, J=7.2 Hz, 1H), 4.62 (d, J=14.9 Hz, 1H), 4.48 (dd, J=12.2, 5.0 Hz, 1H), 4.28 (d, J=15.0 Hz, 1H), 4.18 (dt, J=13.3, 4.9 Hz, 1H), 3.52-3.38 (m, 3H), 3.32 (dt, J=13.6, 6.9 Hz, 1H), 2.91 (dd, J=16.8, 6.2 Hz, 1H), 2.80 (s, 3H), 2.28-2.14 (m, 5H), 1.74-1.61 (m, 3H), 1.45 (s, 1H), 1.24-1.11 (m, 2H).

Example 493: 3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.08 mL, 0.39 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 100 mg, 0.24 mmol), 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59, 81 mg, 0.34 mmol), and triphenylphosphine (92.1 mg, 0.35 mmol) in THF (3 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (70 mg, 46%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₆S, 646.6; m/z found, 646.9 [M]⁺.

Step B: 3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (70 mg, 0.11 mmol), 1 M aqueous NaOH solution (1 mL, 1 mmol), THF (1 mL) and ethanol (0.01 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (53 mg, 79%) as a white foam. This foam was further purified via preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound as a white foam (43 mg, 64%). MS (ESI): mass calcd. for C₂₇H₂₅F₃N₆O₆S, 618.2; m/z found, 618.2 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.57 (dd, J=4.9, 1.9 Hz, 1H), 8.26 (dd, J=7.6, 1.9 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.37 (dd, J=7.6, 4.9 Hz, 1H), 7.04 (t, J=7.2 Hz, 2H), 5.31 (s, 1H), 5.06 (dd, J=9.8, 5.4 Hz, 1H), 4.85 (d, J=7.5 Hz, 2H), 4.72-4.58 (m, 2H), 4.44 (d, J=14.1 Hz, 1H), 4.17-4.07 (m, 2H), 3.91 (d, J=15.4 Hz, 1H), 3.47 (dd, J=16.2, 9.8 Hz, 1H), 2.96-2.86 (m, 1H), 2.84 (s, 3H), 2.39 (s, 3H).

Example 494: (*S)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3M-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 493, 43 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 30% CO₂, 70% MeOH) to afford two enantiomers. The first eluting enantiomer (21 mg) was designated (*S). MS (ESI): mass calcd. for C₂₇H₂₅F₃N₆O₆S, 618.2; m/z found, 618.2 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.57 (dd, J=4.9, 1.9 Hz, 1H), 8.26 (dd, J=7.6, 1.9 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.37 (dd, J=7.6, 4.9 Hz, 1H), 7.04 (t, J=7.2 Hz, 2H), 5.31 (s, 1H), 5.06 (dd, J=9.8, 5.4 Hz, 1H), 4.85 (d, J=7.5 Hz, 2H), 4.72-4.58 (m, 2H), 4.44 (d, J=14.1 Hz, 1H), 4.17-4.07 (m, 2H), 3.91 (d, J=15.4 Hz, 1H), 3.47 (dd, J=16.2, 9.8 Hz, 1H), 2.96-2.86 (m, 1H), 2.84 (s, 3H), 2.39 (s, 3H).

Example 495: (*R)-3-(6-((1′,1′-Dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3M-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (22 mg) from the chiral separation described in Example 494 was designated (*R). MS (ESI): mass calcd. for C₂₇H₂₅F₃N₆O₆S, 618.2; m/z found, 618.2 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.50 (dd, J=4.8, 2.0 Hz, 1H), 8.18 (dd, J=7.7, 1.9 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.29 (dd, J=7.6, 4.9 Hz, 1H), 6.89 (dd, J=21.1, 7.5 Hz, 2H), 5.23 (s, 1H), 5.03-4.94 (m, 1H), 4.80 (dd, J=12.2, 7.4 Hz, 2H), 4.70-4.61 (m, 2H), 4.53 (d, J=7.3 Hz, 1H), 4.31 (d, J=14.0 Hz, 1H), 4.03 (d, J=15.3 Hz, 1H), 3.85 (d, J=15.4 Hz, 1H), 3.65 (q, J=7.1 Hz, 0H), 3.34 (dd, J=16.0, 10.4 Hz, 1H), 2.85-2.76 (m, 1H), 2.76 (s, 3H), 2.33 (s, 3H).

Example 496: 3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.12 mL, 0.59 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 150 mg, 0.34 mmol), (*S)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 78, 137 mg, 0.50 mmol), and triphenylphosphine (138 mg, 0.53 mmol) in THF (4 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (200 mg, 83%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₃F₄N₇O₄S, 675.7; m/z found, 675.8 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.06 (s, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.43 (dd, J=7.7, 1.0 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 4.89 (d, J=15.4 Hz, 1H), 4.64-4.40 (m, 3H), 4.35 (d, J=15.4 Hz, 1H), 3.73 (dq, J=10.4, 6.7 Hz, 1H), 3.62 (dd, J=13.1, 4.5 Hz, 1H), 3.54-3.42 (m, 2H), 3.29-3.22 (m, 1H), 2.83 (s, 3H), 2.59 (d, J=2.3 Hz, 3H), 2.29 (s, 3H), 1.86-1.71 (m, 3H), 1.69-1.62 (m, 1H), 1.57-1.42 (m, 1H), 1.21 (dd, J=7.4, 6.3 Hz, 4H).

Step B: 3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (200 mg, 0.30 mmol), 1 M aqueous NaOH solution (1.5 mL, 1.5 mmol) and THF (1.5 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (180 mg, 94%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₉F₄N₇O₄S, 647.2; m/z found, 647.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J=2.9 Hz, 1H), 7.99 (dd, J=12.0, 7.2 Hz, 1H), 7.80 (td, J=7.7, 2.9 Hz, 1H), 7.47-7.38 (m, 1H), 7.32-7.21 (m, 1H), 7.09-7.05 (m, 1H), 6.44 (s, 1H), 4.72 (dd, J=14.7, 7.0 Hz, 1H), 4.59-4.52 (m, 1H), 4.38-4.32 (m, 1H), 4.31-4.21 (m, 1H), 3.65-3.39 (m, 4H), 3.42-3.22 (m, 1H), 3.09-3.04 (m, 1H), 2.86 (d, J=3.3 Hz, 3H), 2.33-2.27 (m, 3H), 1.82-1.65 (m, 3H), 1.67-1.48 (m, 1H), 1.47-1.38 (m, 1H), 1.22 (s, 1H).

Example 497: (*S)-3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 496, 180 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 70% CO₂, 30% iPrOH) to afford two diastereomers. The first eluting diastereomer (78 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₂₉F₄N₇O₄S, 647.2; m/z found, 647.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J=2.9 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.73 (dd, J=7.4, 3.0 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 4.94 (t, J=7.4 Hz, 1H), 4.63 (d, J=15.2 Hz, 1H), 4.49 (dq, J=10.4, 4.9 Hz, 1H), 4.28 (d, J=15.2 Hz, 1H), 4.17 (dt, J=13.3, 4.8 Hz, 1H), 3.53-3.42 (m, 2H), 3.38 (dd, J=16.2, 7.5 Hz, 1H), 3.29-3.23 (m, 1H), 2.93 (dd, J=16.3, 7.3 Hz, 1H), 2.79 (s, 3H), 2.20 (s, 3H), 1.73-1.63 (m, 2H), 1.54 (dd, J=13.7, 6.5 Hz, 1H), 1.45 (dq, J=10.7, 5.2, 4.7 Hz, 2H), 1.21-1.11 (m, 1H).

Example 498: (*R)-3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting diastereomer (80 mg) from the chiral separation described in Example 497 was designated (*R). MS (ESI): mass calcd. for C₂₉H₂₉F₄N₇O₄S, 647.2; m/z found, 647.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J=3.0 Hz, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.71 (dd, J=7.4, 2.9 Hz, 1H), 7.38-7.32 (m, 1H), 7.18-7.08 (m, 1H), 7.01 (d, J=7.8 Hz, 1H), 4.92 (t, J=7.4 Hz, 1H), 4.63 (d, J=14.3 Hz, 1H), 4.47 (dd, J=12.6, 5.0 Hz, 1H), 4.26-4.14 (m, 2H), 3.95 (dq, J=12.3, 6.1 Hz, 0H), 3.47 (t, J=13.0 Hz, 1H), 3.35-3.30 (m, 2H), 3.24 (dd, J=13.4, 3.7 Hz, 1H), 2.95 (dd, J=16.2, 7.4 Hz, 1H), 2.79 (s, 3H), 2.24 (s, 3H), 1.68-1.58 (m, 1H), 1.47 (dq, J=12.4, 6.2 Hz, 1H), 1.37-1.33 (m, 2H), 1.21-1.07 (m, 2H).

Example 499: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate. Diisopropyl azodicarboxylate (0.20 mL, 1.02 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 250 mg, 0.62 mmol), (*S)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 77, 235 mg, 0.88 mmol), and triphenylphosphine (241 mg, 0.92 mmol) in THF (7 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (380 mg, 94%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₈F₂N₆O₄S, 652.3; m/z found, 652.9 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.16-8.06 (m, 2H), 7.82 (dt, J=2.1, 1.1 Hz, 1H), 7.19-7.03 (m, 4H), 6.83 (dd, J=16.5, 7.2 Hz, 1H), 4.91 (q, J=8.2 Hz, 1H), 4.45-4.40 (m, 2H), 4.24-3.98 (m, 3H), 3.23-3.05 (m, 4H), 2.99-2.92 (m, 1H), 2.79 (d, J=12.0 Hz, 3H), 2.32-2.16 (m, 4H), 1.99 (s, 2H), 1.66-1.60 (m, 4H), 1.50-1.27 (m, 3H), 1.13 (td, J=7.1, 2.3 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate (380 mg, 0.58 mmol), 1 M aqueous NaOH solution (5.4 mL, 5.4 mmol), THF (5.4 mL) and ethanol (0.03 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (348 mg, 96%) as a white foam which was further purified by preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound as a white foam (338 mg, 93%). MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.2; m/z found, 624.2 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.20-8.08 (m, 2H), 7.88 (d, J=2.2 Hz, 1H), 7.24-7.16 (m, 1H), 7.18-7.02 (m, 3H), 6.89 (dd, J=14.2, 7.3 Hz, 1H), 5.31 (s, 1H), 4.95 (q, J=9.2 Hz, 1H), 4.43 (dd, J=17.4, 14.5 Hz, 1H), 4.25-4.20 (m, 1H), 4.15-4.07 (m, 1H), 3.49 (q, J=7.0 Hz, 1H), 3.30-3.19 (m, 1H), 3.21-3.12 (m, 2H), 3.09-3.00 (m, 1H), 2.78 (d, J=10.2 Hz, 3H), 2.33-2.19 (m, 6H), 1.61 (dt, J=12.5, 5.4 Hz, 1H), 1.49 (dt, J=18.8, 7.2 Hz, 2H), 1.44-1.31 (m, 1H), 1.26 (s, 1H), 1.21 (t, J=7.0 Hz, 1H).

Example 500: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid isomers (Example 499, 338 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 45% CO₂, 55% MeOH) to afford two diastereomers. The first eluting isomer (157 mg) was designated (*S). MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.2; m/z found, 624.2 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.09-8.02 (m, 2H), 7.79 (d, J=2.2 Hz, 1H), 7.12 (d, J=2.3 Hz, 2H), 7.08-6.95 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 5.22 (s, 1H), 4.86 (t, J=7.8 Hz, 1H), 4.33 (dd, J=14.8, 5.5 Hz, 2H), 4.17 (d, J=14.9 Hz, 1H), 4.05 (dt, J=13.3, 4.8 Hz, 1H), 3.17 (d, J=2.0 Hz, 1H), 3.15 (s, 1H), 3.16-3.01 (m, 2H), 2.94 (dd, J=15.9, 8.8 Hz, 1H), 2.69 (s, 3H), 2.18 (d, J=6.6 Hz, 6H), 1.61-1.49 (m, 1H), 1.45-1.27 (m, 4H), 1.21-1.12 (m, 1H).

Example 501: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

The second eluting isomer (145 mg) from the chiral separation described in Example 500 was designated (*R). MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.2; m/z found, 624.2 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.08-8.03 (m, 2H), 7.79 (d, J=2.2 Hz, 1H), 7.19 (s, 1H), 7.15-6.98 (m, 3H), 6.76 (d, J=7.2 Hz, 1H), 5.84 (s, 1H), 4.88 (s, 1H), 4.38-4.32 (m, 2H), 4.11 (d, J=14.7 Hz, 1H), 4.04 (dt, J=13.3, 4.9 Hz, 1H), 3.11-3.07 (m, 3H), 2.94 (s, 1H), 2.72 (s, 3H), 2.19 (s, 6H), 1.56 (dd, J=9.9, 5.4 Hz, 2H), 1.43 (s, 1H), 1.36-1.22 (m, 1H), 1.18 (s, 1H), 1.16 (d, J=6.8 Hz, 1H).

Example 502: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate. Diisopropyl azodicarboxylate (0.22 mL, 1.14 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 280 mg, 0.69 mmol), (*R)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 117, 264 mg, 0.99 mmol), and triphenylphosphine (270 mg, 1.03 mmol) in THF (8 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (450 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₈F₂N₆O₄S, 652.8; m/z found, 652.9 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.14-8.04 (m, 2H), 7.85-7.80 (m, 1H), 7.18-7.02 (m, 4H), 6.83 (dd, J=17.5, 7.2 Hz, 1H), 4.89 (td, J=9.0, 6.9 Hz, 1H), 4.46-4.32 (m, 2H), 4.23-3.96 (m, 4H), 3.26-3.03 (m, 4H), 2.99-2.96 (m, 1H), 2.77 (d, J=12.7 Hz, 3H), 2.28-2.14 (m, 3H), 1.97 (s, 3H), 1.70-1.26 (m, 3H), 1.26-1.03 (m, 6H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate (450 mg, 0.69 mmol), 1 M aqueous NaOH solution (6.4 mL, 6.4 mmol), THF (6.4 mL) and ethanol (0.04 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (428 mg, 99%) as a white foam which was further purified by preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound (418 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.2; m/z found, 624.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.20-8.08 (m, 2H), 7.88 (d, J=2.3 Hz, 1H), 7.24-7.16 (m, 1H), 7.18-7.02 (m, 3H), 6.89 (dd, J=14.6, 7.3 Hz, 1H), 6.72 (s, 1H), 4.96 (td, J=9.7, 6.6 Hz, 1H), 4.48-4.37 (m, 2H), 4.24-4.20 (m, 1H), 4.14-4.07 (m, 1H), 3.30-3.12 (m, 4H), 3.09-3.02 (m, 1H), 2.78 (d, J=10.8 Hz, 3H), 2.33-2.19 (m, 6H), 1.63-1.59 (m, 1H), 1.53-1.47 (m, 2H), 1.39-1.36 (m, 2H), 1.21 (t, J=7.0 Hz, 1H).

Example 503: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid isomers (Example 502, 418 mg) was purified by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, isocratic mobile phase: 50% CO₂, 50% EtOH) to afford two diastereomers. The first eluting isomer (174 mg) was designated (*S). MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.2; m/z found, 624.9 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.20-8.13 (m, 2H), 7.90 (d, J=2.3 Hz, 1H), 7.26-7.08 (m, 4H), 6.88 (d, J=7.2 Hz, 1H), 6.48 (s, 1H), 4.99 (t, J=7.8 Hz, 1H), 4.52-4.39 (m, 2H), 4.23 (d, J=14.6 Hz, 1H), 4.13 (dt, J=13.2, 4.8 Hz, 1H), 3.19-3.12 (m, 4H), 3.05 (dd, J=15.9, 9.0 Hz, 1H), 2.83 (s, 3H), 2.30 (s, 6H), 1.67-1.63 (m, 2H), 1.45-1.40 (m, 3H), 1.27 (dd, J=9.2, 6.1 Hz, 1H).

Example 504: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

The second eluting isomer (174 mg) from the chiral separation described in Example 503 was designated (*R). MS (ESI): mass calcd. for C₃₁H₃₄F₂N₆O₄S, 624.2; m/z found, 624.9 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.03 (m, 2H), 7.80 (d, J=2.3 Hz, 1H), 7.15-6.96 (m, 4H), 6.79 (d, J=7.2 Hz, 1H), 6.47 (s, 1H), 4.86 (t, J=7.8 Hz, 1H), 4.40-4.28 (m, 2H), 4.17 (d, J=14.9 Hz, 1H), 4.04 (dt, J=13.2, 4.9 Hz, 1H), 3.23-3.13 (m, 2H), 3.09-3.02 (m, 2H), 2.96 (t, J=12.5 Hz, 1H), 2.70 (s, 3H), 2.18 (d, J=6.1 Hz, 6H), 1.59-1.53 (m, 2H), 1.38-1.33 (m, 1H), 1.30 (s, 2H), 1.26 (s, 1H).

Example 505: 3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of LDA (1.07 mL, 2 M in THF/heptane/ethylbenzene, 2.13 mmol) was added dropwise at −78° C. to ethyl 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 496, Step A, 1.20 g, 1.78 mmol) in THF (23 mL) and the resulting mixture was stirred for 0.5 hour. Iodomethane (0.44 mL, 7.10 mmol) was added dropwise and the resulting solution was warmed to room temperature over a period of 2 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 30% DCM/EtOAc) to provide the title compound (450 mg, 37%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₅F₄N₇O₄S, 689.2; m/z found, 689.9 [M+H]⁺.

Step B: 3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (110 mg, 0.16 mmol), 1 M aqueous NaOH solution (1.5 mL, 1.5 mmol), THF (1.5 mL) and ethanol (0.05 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% DCM/MeOH) to provide the title compound (100 mg, 95%) as a white foam. This foam was further purified by preparative LC (Stationary phase: irregular bare silica 40 g, Mobile phase: 97% DCM, 3% MeOH) to provide the title compound (100 mg, 95%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₁F₄N₇O₄S, 661.2; m/z found, 661.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.22 (dd, J=3.0, 2.2 Hz, 1H), 8.01 (dd, J=15.1, 7.3 Hz, 1H), 7.88-7.76 (m, 2H), 7.49-7.44 (m, 1H), 7.15 (dd, J=15.1, 7.7 Hz, 1H), 5.31 (s, 1H), 4.75 (d, J=15.1 Hz, 1H), 4.66-4.55 (m, 2H), 4.44-4.24 (m, 2H), 3.86-3.69 (m, 1H), 3.59-3.47 (m, 2H), 3.49-3.34 (m, 1H), 2.78 (d, J=10.0 Hz, 3H), 2.29 (s, 3H), 1.81 (dt, J=13.9, 7.0 Hz, 2H), 1.73-1.49 (m, 3H), 1.31-1.12 (m, 4H).

Example 506: (3*S)-3-(6-(((S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 505, 100 mg) were separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 30% CO₂, 70% MeOH) to afford two diasteromers. The first eluting diastereomer (40 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₁F₄N₇O₄S, 661.2; m/z found, 661.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=3.0 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.83 (dd, J=7.4, 2.9 Hz, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.47-7.41 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 5.31 (s, 1H), 4.73 (d, J=15.3 Hz, 1H), 4.64-4.52 (m, 2H), 4.40 (d, J=15.3 Hz, 1H), 4.28 (dt, J=13.4, 4.8 Hz, 1H), 3.79-3.69 (m, 1H), 3.58 (t, J=4.5 Hz, 1H), 3.55-3.43 (m, 1H), 3.39-3.32 (m, 1H), 2.78 (s, 3H), 2.29 (s, 3H), 1.87-1.71 (m, 2H), 1.65 (dq, J=12.2, 6.1 Hz, 2H), 1.57-1.51 (m, 2H), 1.29-1.12 (m, 3H).

Example 507: (3*R)-3-(6-(((*S)-3-Fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (50 mg) from the chiral separation described in Example 506 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₁F₄N₇O₄S, 661.2; m/z found, 661.9 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=2.9 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.82 (dd, J=7.4, 3.0 Hz, 1H), 7.69 (d, J=7.3 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 5.68 (s, 1H), 4.72 (d, J=15.2 Hz, 1H), 4.57 (t, J=9.8 Hz, 2H), 4.38 (d, J=15.3 Hz, 1H), 4.27 (dt, J=13.3, 4.7 Hz, 1H), 3.74 (dq, J=10.4, 6.7 Hz, 1H), 3.61-3.58 (m, 1H), 3.54-3.41 (m, 1H), 3.39-3.35 (m, 1H), 2.79 (s, 3H), 2.28 (s, 3H), 1.84-1.76 (m, 2H), 1.79-1.70 (m, 1H), 1.74-1.56 (m, 1H), 1.58-1.46 (m, 2H), 1.18 (d, J=6.8 Hz, 3H).

Example 508: 3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.38 mL, 1.95 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 500 mg, 1.18 mmol), 8′-fluoro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 80, 411 mg, 1.68 mmol), and triphenylphosphine (460 mg, 1.76 mmol) in THF (13 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (700 mg, 91%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₈F₄N₆O₅S, 648.2; m/z found, 649.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (d, J=3.0 Hz, 1H), 8.02-7.85 (m, 2H), 7.44 (dd, J=7.8, 0.9 Hz, 1H), 7.09-7.05 (m, 2H), 4.95 (dd, J=8.1, 7.0 Hz, 1H), 4.55-4.33 (m, 2H), 4.13-3.95 (m, 3H), 3.29 (dd, J=16.1, 8.2 Hz, 1H), 2.93-2.74 (m, 3H), 2.37 (s, 3H), 2.00 (s, 2H), 1.28-1.04 (m, 3H), 0.91-0.88 (m, 2H), 0.82-0.69 (m, 2H).

Step B: 3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (700 mg, 1.08 mmol), 1 M aqueous NaOH solution (10 mL, 10 mmol) and THF (10 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (657 mg, 98%) as a white foam. This foam was further purified by preparative LC (Stationary phase: irregular 15-40 μm 50 g Merck, Mobile phase: 0.4% H₂O, 95% DCM, 5% MeOH) to provide the title compound (537 mg, 80%) as a white foam. MS (ESI): mass calcd. for C₂₇H₂₄F₄N₆O₅S, 620.6; m/z found, 621.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.73 (s, 1H), 8.30 (d, J=3.1 Hz, 1H), 8.04 (dd, J=6.4, 3.1 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.49-7.42 (m, 1H), 7.08 (dd, J=15.3, 7.6 Hz, 2H), 4.99 (t, J=7.5 Hz, 1H), 4.56 (d, J=13.6 Hz, 1H), 4.43 (d, J=13.7 Hz, 1H), 3.80 (d, J=15.9 Hz, 1H), 3.49 (q, J=7.0 Hz, 1H), 3.40 (dd, J=16.4, 8.1 Hz, 1H), 2.95 (dd, J=16.4, 6.9 Hz, 1H), 2.82 (s, 3H), 2.40 (s, 3H), 1.28-1.16 (m, 1H), 1.18-1.10 (m, 1H), 0.99-0.90 (m, 1H), 0.76 (dt, J=10.7, 6.3 Hz, 1H).

Example 509: (*S)-3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(6-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 508, 537 mg) was separated by chiral SFC (Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford two enantiomers. The first eluting enantiomer (233 mg) was designated (*S). MS (ESI): mass calcd. for C₂₇H₂₄F₄N₆O₅S, 620.6; m/z found, 621.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=3.1 Hz, 1H), 8.05 (dd, J=6.4, 3.0 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.49-7.44 (m, 1H), 7.09-7.05 (m, 2H), 5.99 (s, 2H), 4.99 (t, J=7.5 Hz, 1H), 4.58 (d, J=13.7 Hz, 1H), 4.43 (d, J=13.7 Hz, 1H), 3.83 (s, 1H), 3.40 (dd, J=16.4, 8.0 Hz, 1H), 2.95 (dd, J=16.4, 7.0 Hz, 1H), 2.83 (s, 3H), 2.41 (s, 3H), 1.26-1.22 (m, 1H), 1.11 (dt, J=11.4, 6.4 Hz, 1H), 0.96 (t, J=6.7 Hz, 1H), 0.73 (dt, J=10.7, 6.6 Hz, 1H).

Example 510: (*R)-3-(6-((8′-Fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting enantiomer (225 mg) from the chiral separation described in Example 509 was designated (*R). MS (ESI): mass calcd. for C₂₇H₂₄F₄N₆O₅S, 620.6; m/z found, 621.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=3.1 Hz, 1H), 8.06 (dd, J=6.4, 3.1 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.04 (d, J=7.3 Hz, 1H), 5.31 (s, 2H), 4.99 (t, J=7.5 Hz, 1H), 4.59 (d, J=13.7 Hz, 1H), 4.43 (d, J=13.6 Hz, 1H), 3.83 (s, 1H), 3.40 (dd, J=16.4, 8.0 Hz, 1H), 2.95 (dd, J=16.4, 6.9 Hz, 1H), 2.84 (s, 3H), 2.41 (s, 3H), 1.29-1.20 (m, 1H), 1.12 (dt, J=11.5, 6.5 Hz, 1H), 0.96 (s, 1H), 0.73 (dt, J=10.7, 6.6 Hz, 1H).

Example 511: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.40 mL, 2.04 mmol) was added to a stirring mixture of ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Intermediate 167, 500 mg, 1.24 mmol), (*S)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 78, 478 mg, 1.76 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (14 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (750 mg, 92%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₅F₆N₆O₄S, 656.7; m/z found, 656.9 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.19-8.12 (m, 2H), 7.79 (dd, J=7.4, 3.0 Hz, 1H), 7.17-7.07 (m, 3H), 6.86 (d, J=7.2 Hz, 1H), 4.93 (dd, J=8.8, 6.9 Hz, 1H), 4.49-4.39 (m, 2H), 4.24 (d, J=14.8 Hz, 1H), 4.18-4.03 (m, 4H), 3.30-3.08 (m, 4H), 3.01 (dd, J=15.9, 8.8 Hz, 1H), 2.81 (s, 3H), 2.24 (s, 3H), 1.79-1.56 (m, 3H), 1.58-1.32 (m, 3H), 1.16 (t, J=7.1 Hz, 3H).

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*S)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate (550 mg, 0.84 mmol), 1 M aqueous NaOH solution (7.7 mL, 7.7 mmol) and THF (7.7 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (504 mg, 95%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.7; m/z found, 629.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.60 (s, 1H), 8.22-8.12 (m, 2H), 7.80 (dd, J=7.4, 3.0 Hz, 1H), 7.23-7.06 (m, 4H), 6.92 (d, J=7.3 Hz, 1H), 5.30 (s, 1H), 4.96 (dd, J=9.1, 6.6 Hz, 1H), 4.47-4.34 (m, 2H), 4.26 (d, J=14.9 Hz, 1H), 4.11 (dt, J=13.4, 5.0 Hz, 1H), 3.33-3.03 (m, 5H), 2.77 (s, 3H), 2.25 (s, 3H), 1.77-1.56 (m, 2H), 1.55-1.31 (m, 3H).

Example 512: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate. Diisopropyl azodicarboxylate (0.40 mL, 2.04 mmol) was added to a stirring mixture of ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Intermediate 167, 500 mg, 1.24 mmol), (*S)-3-fluoro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 79, 478 mg, 1.76 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (14 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (600 mg, 74%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₅F₆N₆O₄S, 656.7; m/z found, 657.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.16-8.10 (m, 2H), 7.75 (dd, J=7.4, 2.9 Hz, 1H), 7.19-7.05 (m, 4H), 6.83 (d, J=7.2 Hz, 1H), 4.92 (dd, J=8.8, 6.9 Hz, 1H), 4.48-4.32 (m, 2H), 4.22-3.96 (m, 5H), 3.24-3.05 (m, 4H), 2.99 (dd, J=15.8, 8.9 Hz, 1H), 2.80 (s, 3H), 2.24 (s, 3H), 1.72-1.48 (m, 2H), 1.46-1.05 (m, 6H).

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(((*R)-3-fluoro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoate (600 mg, 0.91 mmol), 1 M aqueous NaOH solution (8.4 mL, 8.4 mmol) and THF (8.4 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (550 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₄S, 628.7; m/z found, 629.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.44 (s, 1H), 8.19-8.11 (m, 2H), 7.79 (dd, J=7.4, 3.0 Hz, 1H), 7.25-7.08 (m, 4H), 6.91 (d, J=7.3 Hz, 1H), 5.29 (s, 1H), 4.97 (dd, J=9.1, 6.5 Hz, 1H), 4.50-4.34 (m, 2H), 4.25-4.03 (m, 2H), 3.32-3.02 (m, 5H), 2.78 (s, 3H), 2.26 (s, 3H), 1.72-1.53 (m, 2H), 1.48-1.20 (m, 3H).

Example 513: (3*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

Step A: Ethyl (*S)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.77 mL, 3.91 mmol) was added to a stirring mixture of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 1.00 g, 2.37 mmol), (*S)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 77, 901 mg, 3.37 mmol), and triphenylphosphine (923 mg, 3.52 mmol) in THF (27 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.3 g, 82%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₄S, 670.8; m/z found, 671.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.13 (dd, J=2.3, 0.8 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.86 (dd, J=2.3, 0.9 Hz, 1H), 7.21-7.09 (m, 2H), 7.07 (dd, J=7.9, 2.0 Hz, 1H), 6.92 (d, J=7.3 Hz, 1H), 4.94 (dd, J=9.0, 6.8 Hz, 1H), 4.53-4.35 (m, 2H), 4.29-3.99 (m, 4H), 3.32-2.96 (m, 5H), 2.84 (d, J=0.7 Hz, 3H), 2.26 (d, J=8.5 Hz, 6H), 1.81-1.60 (m, 3H), 1.59-1.37 (m, 3H), 1.23-1.18 (m, 3H).

Step B: Ethyl (3*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate. A solution of LDA (2.91 mL, 1 M in hexane/THF, 2.91 mmol) was added dropwise at −78° C. to ethyl (*S)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.30 g, 1.94 mmol) in THF (25 mL) and the resulting mixture was stirred for 0.5 hour. Iodomethane (0.24 mL, 3.88 mmol) was added dropwise and the resulting solution was warmed to room temperature over a period of 2 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 30% DCM/EtOAc) to provide the title compound (150 mg, 11%) as a white foam. MS (ESI): mass calcd. for C₃₅H₄₁F₃N₆O₄S, 698.8; m/z found, 699.3 [M+H]⁺.

Step C: (3*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl (3*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate (150 mg, 0.21 mmol), 1 M aqueous NaOH solution (2 mL, 2 mmol) and THF (2 mL) was stirred at 50° C. overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (113 mg, 79%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₄S, 670.8; m/z found, 671.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.14 (d, J=2.3 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.88 (dd, J=2.2, 0.9 Hz, 1H), 7.31-7.25 (m, 2H), 7.20-7.12 (m, 2H), 4.51-4.40 (m, 3H), 4.24 (d, J=15.0 Hz, 1H), 4.20-4.09 (m, 1H), 3.38-3.17 (m, 6H), 2.26 (d, J=18.9 Hz, 6H), 2.05 (d, J=6.0 Hz, 1H), 1.77-1.60 (m, 3H), 1.56-1.46 (m, 1H), 1.46-1.29 (m, 2H), 1.30-1.23 (m, 6H).

Example 514: (3*S)-2-Methyl-3-(4-methyl-34(*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (3*S)-2-methyl-3-(4-methyl-34(*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of LDA (2.91 mL, 1 M in hexane/THF, 2.91 mmol) was added dropwise at −78° C. to ethyl (*S)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 513, Step A, 1.30 g, 1.94 mmol) in THF (25 mL) and the resulting mixture was stirred for 0.5 hour. Iodomethane (0.24 mL, 3.88 mmol) was added dropwise and the resulting solution was warmed to room temperature over a period of 2 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 30% DCM/EtOAc) to provide the title compound (200 mg, 15%) as a white foam. MS (ESI): mass calcd. for C₃₄H₃₉F₃N₆O₄S, 684.8; m/z found, 685.3 [M+H]⁺.

Step B: (3*S)-2-Methyl-3-(4-methyl-34(*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl (3*S)-2-methyl-3-(4-methyl-34(*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (200 mg, 0.29 mmol), 1 M aqueous NaOH solution (2.7 mL, 2.7 mmol) and THF (2.7 mL) was stirred at 50° C. overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (113 mg, 79%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.2; m/z found, 656.2 [M]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.17-8.12 (m, 1H), 8.06-7.99 (m, 1H), 7.91-7.86 (m, 1H), 7.28-7.18 (m, 2H), 7.15 (d, J=1.4 Hz, 2H), 4.52-4.47 (m, 1H), 4.49-4.43 (m, 1H), 4.45-4.38 (m, 1H), 4.26 (d, J=15.0 Hz, 1H), 4.19 (dt, J=13.3, 4.9 Hz, 1H), 3.49 (q, J=7.0 Hz, 2H), 3.37 (dq, J=11.2, 6.7 Hz, 1H), 3.32-3.19 (m, 3H), 2.76 (s, 3H), 2.31-2.20 (m, 4H), 1.81-1.63 (m, 1H), 1.58-1.52 (m, 1H), 1.49-1.31 (m, 2H), 1.27 (d, J=6.9 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H).

Example 515: (3*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

Step A: Ethyl (*S)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.77 mL, 3.91 mmol) was added to a stirring mixture of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 1.00 g, 2.37 mmol), (*R)-3-methyl-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 117 901 mg, 3.37 mmol), and triphenylphosphine (923 mg, 3.52 mmol) in THF (27 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.4 g, 88%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₄S, 670.8; m/z found, 671.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (dd, J=2.3, 0.9 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.85 (dd, J=2.3, 0.9 Hz, 1H), 7.18-7.04 (m, 3H), 6.90 (d, J=7.3 Hz, 1H), 4.95 (dd, J=9.0, 6.8 Hz, 1H), 4.48-4.35 (m, 2H), 4.25-3.99 (m, 4H), 3.25-3.06 (m, 4H), 3.00 (dd, J=15.8, 9.1 Hz, 1H), 2.85 (s, 3H), 2.27 (d, J=2.9 Hz, 6H), 1.78-1.55 (m, 3H), 1.54-1.09 (m, 6H).

Step B: Ethyl (3*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate. A solution of LDA (3.13 mL, 1 M in hexane/THF, 3.13 mmol) was added dropwise at −78° C. to ethyl (*S)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.40 g, 2.09 mmol) in THF (25 mL) and the resulting mixture was stirred for 0.5 hour. Iodomethane (0.26 mL, 4.17 mmol) was added dropwise and the resulting solution was warmed to room temperature over a period of 2 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by preparative acidic HPLC (0.05% TFA in water, 0.05% TFA in acetonitrile) to provide the title compound (300 mg, 21%) as a white foam. MS (ESI): mass calcd. for C₃₅H₄₁F₃N₆O₄S, 698.3; m/z found, 699.3 [M+H]⁺.

Step C: (3*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl (3*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-methyl-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate (250 mg, 0.36 mmol), 1 M aqueous NaOH solution (3.3 mL, 3.3 mmol) and THF (3.3 mL) was stirred at 50° C. overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (133 mg, 48%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₄S, 670.8; m/z found, 671.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 9.33 (s, 2H), 8.13 (d, J=2.3 Hz, 1H), 8.06-7.98 (m, 1H), 7.90-7.84 (m, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.19-7.07 (m, 2H), 4.47 (d, J=11.4 Hz, 1H), 4.45-4.35 (m, 2H), 4.34 (d, J=11.3 Hz, 1H), 4.25 (d, J=14.9 Hz, 1H), 4.22-4.10 (m, 1H), 3.39-3.13 (m, 5H), 2.25 (d, J=17.6 Hz, 6H), 1.75-1.63 (m, 1H), 1.64-1.61 (m, 1H), 1.54-1.45 (m, 1H), 1.39-1.36 (m, 2H), 1.29-1.20 (m, 5H), 1.17 (d, J=6.9 Hz, 1H).

Example 516: (*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

Step A: Ethyl (*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate. A solution of LDA (3.13 mL, 1 M in hexane/THF, 3.13 mmol) was added dropwise at −78° C. to ethyl (*S)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 515, Step A, 1.40 g, 2.09 mmol) in THF (25 mL) and the resulting mixture was stirred for 0.5 hour. Iodomethane (0.26 mL, 4.17 mmol) was added dropwise and the resulting solution was warmed to room temperature over a period of 2 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by preparative acidic HPLC (0.05% TFA in water, 0.05% TFA in acetonitrile) to provide the title compound (70 mg, 5%) as a white foam. MS (ESI): mass calcd. for C₃₄H₃₉F₃N₆O₄S, 684.8; m/z found, 685.3 [M+H]⁺.

Step B: (*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl (*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*R)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate (70 mg, 0.1 mmol), 1 M aqueous NaOH solution (0.9 mL, 0.9 mmol) and THF (0.9 mL) was stirred at 50° C. overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (33 mg, 49%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.7; m/z found, 657.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.12 (d, J=2.2 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.86 (t, J=2.7 Hz, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.18-7.06 (m, 2H), 6.91 (d, J=7.3 Hz, 1H), 5.00-4.89 (m, 1H), 4.51-4.35 (m, 2H), 4.20 (dd, J=14.9, 4.7 Hz, 1H), 4.09 (dt, J=13.3, 4.9 Hz, 1H), 3.39-3.19 (m, 2H), 3.22-3.10 (m, 3H), 3.06-2.94 (m, 1H), 2.78 (s, 1H), 2.69 (s, 1H), 2.27 (s, 1H), 2.26 (s, 6H), 2.05 (s, 1H), 1.69-1.58 (m, 2H), 1.55-1.40 (m, 1H), 1.42-1.23 (m, 4H).

Example 517: (*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid

Step A: Ethyl (*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate. A solution of LDA (2.91 mL, 1 M in hexane/THF, 2.91 mmol) was added dropwise at −78° C. to ethyl (*S)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 513, Step A, 1.30 g, 1.94 mmol) in THF (25 mL) and the resulting mixture was stirred for 0.5 hour. Iodomethane (0.24 mL, 3.88 mmol) was added dropwise and the resulting solution was warmed to room temperature over a period of 2 hours. The mixture was quenched with aqueous saturated NaHCO₃ solution (10 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). These extractions resulted in several organic solvent fractions which were combined and concentrated to dryness under reduced pressure. The residue was purified by preparative acidic HPLC (0.05% TFA in water, 0.05% TFA in acetonitrile) to provide the title compound (80 mg, 6%) as a white foam. MS (ESI): mass calcd. for C₃₄H₃₉F₃N₆O₄S, 684.8; m/z found, 685.3 [M+H]⁺.

Step B: (*S)-3-(8-Ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-(((*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl (*S)-3-(8-ethyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-34(*S)-3-methyl-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)phenyl)propanoate (80 mg, 0.12 mmol), 1 M aqueous NaOH solution (2.7 mL, 2.7 mmol) and THF (2.7 mL) was stirred at 50° C. overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (39 mg, 45%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₄S, 656.2; m/z found, 657.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.17-8.12 (m, 1H), 8.06-7.99 (m, 1H), 7.91-7.86 (m, 1H), 7.28-7.18 (m, 2H), 7.15 (d, J=1.4 Hz, 2H), 4.52-4.47 (m, 1H), 4.49-4.43 (m, 1H), 4.45-4.38 (m, 1H), 4.26 (d, J=15.0 Hz, 1H), 4.19 (dt, J=13.3, 4.9 Hz, 1H), 3.49 (q, J=7.0 Hz, 2H), 3.37 (dq, J=11.2, 6.7 Hz, 1H), 3.32-3.19 (m, 3H), 2.76 (s, 3H), 2.31-2.20 (m, 6H), 1.81-1.63 (m, 1H), 1.56-1.54 (m, 1H), 1.49-1.31 (m, 2H), 1.27 (d, J=6.9 Hz, 1H), 1.21 (t, J=7.0 Hz, 3H).

Example 518: 3-(6-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(6-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DBAD (303 mg, 1.32 mmol) was added to a stirring mixture of ethyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Example 33, Step B, 367 mg, 0.87 mmol), 3-chloro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 152 300 mg, 1.04 mmol), and triphenylphosphine (343 mg, 1.31 mmol) in THF (11 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (550 mg, 91%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₃ClF₃N₇O₄S, 692.2; m/z found, 692.2 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=2.5 Hz, 1H), 8.06-7.97 (m, 2H), 7.44 (dd, J=13.8, 7.8 Hz, 1H), 7.35-7.18 (m, 1H), 7.12 (dd, J=21.0, 7.8 Hz, 1H), 5.05 (q, J=7.2 Hz, 1H), 4.79-4.57 (m, 2H), 4.40-4.24 (m, 2H), 4.20-3.99 (m, 3H), 3.64-3.50 (m, 2H), 3.49-3.30 (m, 2H), 3.09-3.03 (m, 1H), 2.92 (d, J=2.2 Hz, 3H), 2.34 (s, 1H), 2.28 (s, 2H), 1.87-1.68 (m, 3H), 1.72-1.51 (m, 2H), 1.18 (t, J=7.1 Hz, 3H).

Step B: 3-(6-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(6-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (550 mg, 0.80 mmol), 1 M aqueous NaOH solution (2.4 mL, 2.4 mmol) and THF (20 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (487 mg, 92%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₉ClF₃N₇O₄S, 663.2; m/z found, 664.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H), 8.21 (dd, J=2.3, 1.3 Hz, 1H), 8.05-7.95 (m, 2H), 7.48-7.31 (m, 1H), 7.25 (d, J=7.3 Hz, 1H), 7.08 (dd, J=21.3, 7.8 Hz, 1H), 5.03 (t, J=7.4 Hz, 1H), 4.73 (dd, J=14.8, 9.9 Hz, 1H), 4.66-4.60 (m, 1H), 4.39-4.24 (m, 2H), 3.67-3.22 (m, 4H), 3.09-3.02 (m, 1H), 2.86 (d, J=3.0 Hz, 3H), 2.33 (s, 2H), 2.26 (s, 1H), 1.84-1.65 (m, 2H), 1.55-1.50 (m, 2H), 1.19 (t, J=7.0 Hz, 2H).

Example 519: (*S)-3-(6-(((*S)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 4 diastereomers of 3-(6-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 518, 487 mg) was separated using two chiral separation methods. The mixture of 4 diastereomers was initially subjected to Chiral Separation Method VII: chiral SFC (stationary phase: Daicel Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 45% CO₂, 55% EtOH) to provide Example 519 and Example 520 and a mixture of the two remaining diastereomers (Example 521 and Example 522). The mixture of Example 521 and Example 522 was subsequently separated using Chiral Separation Method VIII: chiral SFC (stationary phase: Daicel Chiralpak IG 5 μm 250×20 mm, Mobile phase: 60% CO₂, 40% EtOH) to afford Example 521 and Example 522. The chiral separation method, order of elution and designated stereochemistry is tabulated below in Table 6. When the stereochemical configuration is written as, for example (*S, *R), with the first configuration, (*S), corresponds to the configuration at the 3-propanoic carbon and the second configuration, (*R), corresponds to the stereochemistry at the sultam. The characterization for (*S)-3-(6-(((*S)-3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 519, 92 mg) is as follows: MS (ESI): mass calcd. for C₂₉H₂₉ClF₃N₇O₄S, 663.2; m/z found, 664.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.03-7.97 (m, 2H), 7.43-7.37 (m, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 5.03 (t, J=7.4 Hz, 1H), 4.75 (d, J=15.6 Hz, 1H), 4.64 (dt, J=9.7, 5.2 Hz, 1H), 4.36-4.28 (m, 2H), 3.64-3.47 (m, 3H), 3.35 (dt, J=13.8, 7.1 Hz, 1H), 3.02 (dd, J=16.5, 6.6 Hz, 1H), 2.88 (s, 3H), 2.27 (s, 3H), 1.77 (dt, J=9.9, 6.0 Hz, 3H), 1.66-1.53 (m, 1H), 1.49 (d, J=17.6 Hz, 1H), 1.27-1.21 (m, 1H).

TABLE 6 Chiral separation method, Order of elution and Designated stereochemistry for Examples 519-522 Chiral Separation Example # method/order of elution Configuration 519 Method VII, second eluting (*S, *S) 520 Method VII, third eluting (*S, *R) 521 Method VIII, first eluting (*R, *S) 522 Method VIII, second eluting (*R, *R)

Example 520: (*S)-3-(6-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (124 mg) was obtained as described in Example 519 and Table 6. MS (ESI): mass calcd. for C₂₉H₂₉ClF₃N₇O₄S, 663.2; m/z found, 664.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.01-7.94 (m, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 5.01 (t, J=7.4 Hz, 1H), 4.72 (d, J=14.2 Hz, 1H), 4.61 (dq, J=13.9, 4.5 Hz, 1H), 4.35-4.24 (m, 2H), 3.58-3.37 (m, 3H), 3.29 (dd, J=13.4, 3.7 Hz, 1H), 3.08 (dd, J=16.5, 7.3 Hz, 1H), 2.86 (s, 3H), 2.33 (s, 3H), 1.76 (td, J=10.4, 4.7 Hz, 2H), 1.54 (h, J=7.7, 6.9 Hz, 1H), 1.45 (tt, J=10.8, 5.9 Hz, 2H), 1.27-1.20 (m, 1H).

Example 521: (*R)-3-(6-(((*S)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (75 mg) was obtained as described in Example 519 and Table 6. MS (ESI): mass calcd. for C₂₉H₂₉ClF₃N₇O₄S, 663.2; m/z found, 664.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.02-7.94 (m, 2H), 7.42-7.37 (m, 1H), 7.29-7.20 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 5.01 (t, J=7.4 Hz, 1H), 4.72 (d, J=15.4 Hz, 1H), 4.61 (dd, J=11.4, 5.4 Hz, 1H), 4.31 (dd, J=14.4, 3.3 Hz, 2H), 3.60-3.50 (m, 2H), 3.52-3.40 (m, 1H), 3.33 (dt, J=13.8, 7.0 Hz, 1H), 3.00 (dd, J=16.2, 7.4 Hz, 1H), 2.86 (s, 3H), 2.26 (s, 3H), 1.80-1.69 (m, 2H), 1.61 (dd, J=13.8, 6.7 Hz, 1H), 1.54 (dd, J=9.0, 4.8 Hz, 1H), 1.25 (s, 1H), 0.99 (d, J=5.9 Hz, 1H).

Example 522: (*R)-3-(6-(((*R)-3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-5-methylpyridin-2-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The title compound (141 mg) was obtained as described in Example 519 and Table 6. MS (ESI): mass calcd. for C₂₉H₂₉ClF₃N₇O₄S, 663.2; m/z found, 664.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=2.5 Hz, 1H), 8.02-7.93 (m, 2H), 7.42 (d, J=7.7 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.99 (t, J=7.4 Hz, 1H), 4.76 (s, 1H), 4.71 (d, J=14.3 Hz, 1H), 4.63-4.56 (m, 1H), 4.30 (dt, J=13.2, 4.7 Hz, 1H), 4.24 (d, J=14.3 Hz, 1H), 3.52 (t, J=13.0 Hz, 1H), 3.42-3.28 (m, 2H), 3.01 (dd, J=16.2, 7.8 Hz, 1H), 2.85 (s, 3H), 2.30 (s, 3H), 1.69 (td, J=10.8, 6.4 Hz, 1H), 1.51 (dd, J=13.1, 6.4 Hz, 1H), 1.41 (dd, J=9.0, 4.8 Hz, 1H), 1.25 (s, 1H), 0.96 (d, J=5.6 Hz, 2H).

Example 523: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate. Di-tert-butyl azodicarboxylate (DBAD, 368 mg, 1.56 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 421 mg, 1.04 mmol), 8-fluoro-2,2′,3,3′,5′,6′-hexahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran] 1,1-dioxide (Intermediate 165, 300 mg, 1.04 mmol), and triphenylphosphine (411 mg, 1.57 mmol) in THF (10 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (680 mg, 97%) as a white foam. MS (ESI): mass calcd. for C₃₃H₃₅F₃N₄O₆S, 672.7; m/z found, 673.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J=7.2 Hz, 1H), 7.53 (dd, J=7.4, 3.1 Hz, 1H), 7.25-7.13 (m, 3H), 7.16-7.07 (m, 2H), 6.85 (d, J=7.3 Hz, 1H), 4.94 (dd, J=8.7, 7.1 Hz, 1H), 4.50 (d, J=15.2 Hz, 1H), 4.44 (d, J=15.1 Hz, 1H), 4.13-4.01 (m, 3H), 3.66 (t, J=11.3 Hz, 2H), 3.52-3.43 (m, 2H), 3.34 (s, 2H), 3.14 (dd, J=15.9, 7.1 Hz, 1H), 3.03 (dd, J=15.9, 8.7 Hz, 1H), 2.80 (s, 3H), 2.22 (s, 3H), 1.67-1.61 (m, 2H), 1.42-1.32 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate (680 mg, 1.01 mmol), 1 M aqueous NaOH solution (3 mL, 3 mmol) and THF (5 mL) was stirred at room temperature overnight 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (624 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₁F₃N₄O₆S, 644.2; m/z found, 645.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.87 (s, 1H), 8.16 (d, J=7.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.53 (td, J=7.2, 2.2 Hz, 2H), 7.25-7.09 (m, 6H), 6.96 (d, J=7.3 Hz, 1H), 4.97 (t, J=7.8 Hz, 1H), 4.49 (s, 2H), 3.64 (q, J=10.3 Hz, 2H), 3.50 (d, J=10.7 Hz, 1H), 3.44 (s, 2H), 3.20 (dd, J=16.0, 7.1 Hz, 1H), 3.08 (dd, J=16.0, 8.4 Hz, 1H), 2.75 (s, 3H), 2.23 (s, 3H), 1.61 (t, J=11.8 Hz, 2H).

Example 524: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 523, 624 mg) was separated by chiral SFC (stationary phase: ethylpyridine 5 μm 150×30 mm, Mobile phase: 60% CO₂, 40% MeOH), followed by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 50% CO₂, 50% MeOH) to afford two enantiomers. The first eluting isomer (261 mg) was designated (*S). MS (ESI): mass calcd. for C₃₁H₃₁F₃N₄O₆S, 644.2; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=7.1 Hz, 1H), 7.57 (dd, J=7.4, 3.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.19-7.05 (m, 3H), 6.88 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.8 Hz, 1H), 4.53 (d, J=14.9 Hz, 1H), 4.47 (d, J=14.8 Hz, 1H), 3.75-3.59 (m, 3H), 3.51 (s, 1H), 3.47 (s, 1H), 3.40 (s, 2H), 3.14 (dd, J=15.8, 8.3 Hz, 2H), 2.98 (dd, J=15.7, 7.4 Hz, 1H), 2.75 (s, 3H), 2.23 (s, 3H), 1.64 (d, J=14.1 Hz, 1H), 1.58 (d, J=14.3 Hz, 1H).

Example 525: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (258 mg) from the chiral separation described in Example 524 was designated (*R). MS (ESI): mass calcd. for C₃₁H₃₁F₃N₄O₆S, 644.2; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=7.2 Hz, 1H), 7.58 (dd, J=7.4, 3.0 Hz, 1H), 7.27-7.14 (m, 4H), 7.16-7.06 (m, 3H), 6.89 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.8 Hz, 1H), 4.56 (d, J=14.7 Hz, 1H), 4.46 (d, J=14.7 Hz, 1H), 3.70 (dd, J=15.9, 9.2 Hz, 3H), 3.52 (s, 1H), 3.48 (s, 1H), 3.40 (s, 2H), 3.16 (dd, J=15.7, 8.4 Hz, 1H), 3.00 (dd, J=15.4, 7.0 Hz, 1H), 2.76 (s, 3H), 2.24 (s, 3H), 1.65 (d, J=14.1 Hz, 1H), 1.57 (d, J=14.4 Hz, 1H).

Example 526: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H-yl)methyl)-4-methylphenyl)propanoate. Di-tert-butyl azodicarboxylate (437 mg, 1.86 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 500 mg, 1.23 mmol), 8′-fluoro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 80, 303 mg, 1.24 mmol), and triphenylphosphine (488 mg, 1.86 mmol) in THF (10 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (780 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.7; m/z found, 630.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=3.0 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.97 (dd, J=6.5, 3.1 Hz, 1H), 7.21-7.08 (m, 2H), 7.12-7.02 (m, 2H), 6.83 (d, J=7.2 Hz, 1H), 4.90 (t, J=7.9 Hz, 1H), 4.30 (s, 2H), 4.07 (dq, J=14.2, 7.1 Hz, 2H), 3.52 (s, 2H), 3.11 (dd, J=15.8, 7.3 Hz, 1H), 2.99 (dd, J=15.9, 8.4 Hz, 1H), 2.76 (s, 3H), 2.27 (s, 3H), 1.22-1.08 (m, 5H), 0.57-0.45 (m, 2H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8-fluoro-1,1-dioxido-2′,3′,5′,6′-tetrahydrospiro[benzo[b][1,4,5]oxathiazepine-4,4′-pyran]-2(3H)-yl)methyl)-4-methylphenyl)propanoate (780 mg, 1.24 mmol), 1 M aqueous NaOH solution (12.4 mL, 12.4 mmol) and THF (12.4 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (737 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₂₈H₂₆F₃N₅O₅S, 601.2; m/z found, 602.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (d, J=3.0 Hz, 1H), 8.12 (d, J=7.1 Hz, 1H), 7.99 (dd, J=6.4, 3.1 Hz, 1H), 7.18 (s, 1H), 7.14-7.06 (m, 2H), 7.04 (dd, J=7.9, 1.9 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 4.89 (t, J=7.8 Hz, 1H), 4.31 (s, 2H), 3.55 (s, 2H), 3.43 (s, 1H), 3.08 (dd, J=15.9, 7.0 Hz, 1H), 2.96 (dd, J=15.9, 8.4 Hz, 1H), 2.67 (s, 3H), 2.25 (s, 3H), 1.25 (d, J=6.8 Hz, 1H), 1.12 (s, 1H), 0.51 (s, 2H).

Example 527: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 526, 737 mg) was separated by chiral SFC (stationary phase: ethylpyridine 5 μm 150×30 mm, Mobile phase: 60% CO₂, 40% MeOH), followed by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 55% CO₂, 45% MeOH) to afford two enantiomers. The first eluting isomer (309 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₅S, 601.2; m/z found, 602.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=3.0 Hz, 1H), 8.14 (d, J=7.1 Hz, 1H), 8.02 (dd, J=6.3, 3.0 Hz, 1H), 7.18 (d, J=30.3 Hz, 1H), 7.15-7.04 (m, 3H), 6.82 (d, J=7.2 Hz, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.37 (d, J=14.6 Hz, 1H), 4.29 (d, J=14.5 Hz, 1H), 3.56 (s, 2H), 3.16 (dd, J=15.9, 7.1 Hz, 1H), 3.02 (dd, J=16.0, 8.5 Hz, 1H), 2.77 (s, 3H), 2.29 (s, 3H), 1.13 (dt, J=9.6, 5.1 Hz, 1H), 1.10-1.02 (m, 1H), 0.49-0.44 (m, 2H).

Example 528: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (307 mg) from the chiral separation described in Example 527was designated (*R). MS (ESI): mass calcd. for C₂₈H₂₆F₃N₅O₅S, 601.2; m/z found, 602.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=3.1 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 8.01 (dd, J=6.3, 3.0 Hz, 1H), 7.20-7.16 (m, 1H), 7.15-7.04 (m, 3H), 6.83 (d, J=7.3 Hz, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.36 (d, J=14.6 Hz, 1H), 4.29 (d, J=14.6 Hz, 1H), 3.56 (s, 2H), 3.16 (dd, J=16.0, 7.1 Hz, 1H), 3.02 (dd, J=15.9, 8.5 Hz, 1H), 2.76 (s, 3H), 2.29 (s, 3H), 1.16-1.10 (m, 2H), 0.55-0.43 (m, 2H).

Example 529: 3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(3-((8′-chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Di-tert-butyl azodicarboxylate (1.12 g, 4.87 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 1.21 g, 3.00 mmol), 8′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 96, 900 mg, 3.45 mmol), and triphenylphosphine (1.28 g, 4.89 mmol) in THF (45 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.80 g, 93%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀ClF₂N₅O₅S, 646.1; m/z found, 646.2 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 7.18-7.06 (m, 3H), 6.85 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.9 Hz, 1H), 4.34 (s, 2H), 4.16-4.07 (m, 2H), 4.07 (d, J=7.1 Hz, 1H), 3.54 (s, 2H), 3.14 (dd, J=15.9, 7.3 Hz, 1H), 3.02 (dd, J=15.9, 8.5 Hz, 1H), 2.80 (s, 3H), 2.30 (s, 2H), 2.04 (s, 1H), 1.26 (t, J=7.1 Hz, 1H), 1.25-1.14 (m, 4H), 0.62-0.52 (m, 2H).

Step B: 3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(3-((8′-chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (500 mg, 0.77 mmol), 1 M aqueous NaOH solution (3 mL, 3 mmol) and THF (4 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (300 mg, 63%) as an oil. MS (ESI): mass calcd. for C₂₄H₂₆ClF₂N₅O₅S, 618.1; m/z found, 618.1 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.21 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H), 8.17 (d, J=7.1 Hz, 1H), 7.17-7.06 (m, 3H), 6.91 (d, J=7.3 Hz, 1H), 5.30 (s, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.33 (s, 2H), 3.53 (s, 2H), 3.18 (dd, J=16.0, 7.1 Hz, 1H), 3.06 (dd, J=16.0, 8.5 Hz, 1H), 2.74 (s, 3H), 2.29 (s, 3H), 1.15-1.05 (m, 2H), 0.58-0.48 (m, 2H).

Example 530: (*S)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((8′-chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 529, 300 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 55% CO₂, 45% EtOH) to afford two enantiomers. The first eluting isomer (150 mg) was designated (*S). MS (ESI): mass calcd. for C₂₄H₂₆ClF₂N₅O₅S, 618.1; m/z found, 618.1 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.17-7.00 (m, 4H), 6.82 (d, J=7.2 Hz, 1H), 5.30 (s, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.37 (d, J=14.6 Hz, 1H), 4.30 (d, J=14.5 Hz, 1H), 3.56 (d, J=15.5 Hz, 1H), 3.47 (d, J=16.1 Hz, 1H), 3.16 (dd, J=16.0, 7.1 Hz, 1H), 3.02 (dd, J=16.0, 8.6 Hz, 1H), 2.77 (s, 3H), 2.29 (s, 3H), 1.17-1.02 (m, 2H), 0.58-0.45 (m, 2H).

Example 531: (*R)-3-(3-((8′-Chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (150 mg) from the chiral separation described in Example 530 was designated (*R). MS (ESI): mass calcd. for C₂₈H₂₆ClF₂N₅O₅S, 618.1; m/z found, 618.1 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.17-7.03 (m, 4H), 6.81 (d, J=7.3 Hz, 1H), 5.30 (s, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.37 (d, J=14.6 Hz, 1H), 4.30 (d, J=14.6 Hz, 1H), 3.57 (d, J=15.4 Hz, 1H), 3.47 (d, J=15.2 Hz, 1H), 3.16 (dd, J=15.9, 7.1 Hz, 1H), 3.02 (dd, J=15.9, 8.5 Hz, 1H), 2.78 (s, 3H), 2.29 (s, 3H), 1.13 (dt, J=10.3, 5.4 Hz, 1H), 1.07 (dt, J=12.0, 5.3 Hz, 1H), 0.55-0.50 (m, 2H).

Example 532: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate. Di-tert-butyl azodicarboxylate (206 mg, 1.30 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 350 mg, 0.87 mmol), 8′-fluoro-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 166, 300 mg, 1.04 mmol), and triphenylphosphine (341 mg, 1.30 mmol) in THF (10 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (550 mg, 94%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₄F₃N₅O₆S, 673.7; m/z found, 674.2 [M+H]⁺.

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoate (600 mg, 0.89 mmol), 1 M aqueous NaOH solution (3.6 mL, 3.6 mmol), THF (4.4 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (550 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₆S, 645.2; m/z found, 646.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=3.1 Hz, 1H), 8.17 (d, J=7.1 Hz, 1H), 7.93 (dd, J=6.3, 3.1 Hz, 1H), 7.23-7.07 (m, 4H), 6.90 (d, J=7.3 Hz, 1H), 4.94 (t, J=7.8 Hz, 1H), 4.53 (d, J=14.9 Hz, 1H), 4.47 (d, J=14.8 Hz, 1H), 3.94 (qd, J=11.9, 6.0 Hz, 2H), 3.66-3.59 (m, 1H), 3.50 (d, J=44.8 Hz, 4H), 3.17 (dd, J=15.9, 8.1 Hz, 1H), 3.02 (dd, J=15.9, 7.5 Hz, 1H), 2.74 (s, 3H), 2.23 (s, 3H), 1.61 (d, J=13.9 Hz, 1H), 1.58-1.45 (m, 1H), 1.38-1.32 (m, 1H).

Example 533: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid isomers (Example 532, 550 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 50% CO₂, 50% EtOH) to afford two enantiomers. The first eluting isomer (233 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₆S, 645.2; m/z found, 646.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J=3.0 Hz, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.87 (dd, J=6.4, 3.1 Hz, 1H), 7.15-6.96 (m, 4H), 6.77 (d, J=7.3 Hz, 1H), 4.84 (dd, J=9.4, 6.2 Hz, 1H), 4.50 (d, J=14.6 Hz, 1H), 4.40 (d, J=14.7 Hz, 1H), 3.89-3.85 (m, 2H), 3.60 (d, J=11.5 Hz, 1H), 3.46 (s, 5H), 3.04 (dd, J=15.6, 9.7 Hz, 1H), 2.85 (dd, J=15.8, 6.0 Hz, 1H), 2.67 (s, 3H), 2.16 (s, 3H), 1.39 (s, 1H), 1.20-1.11 (m, 1H).

Example 534: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((8′-fluoro-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)propanoic acid

The second eluting isomer (228 mg) from the chiral separation described in Example 533 was designated (*R). MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₆S, 645.2; m/z found, 646.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J=3.0 Hz, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.95 (dd, J=6.4, 3.1 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.26-7.02 (m, 4H), 6.88 (d, J=7.2 Hz, 1H), 4.94 (dd, J=8.9, 6.7 Hz, 1H), 4.58 (d, J=14.7 Hz, 1H), 4.47 (d, J=14.6 Hz, 1H), 4.02-3.89 (m, 2H), 3.72-3.68 (m, 1H), 3.58-3.52 (m, 3H), 3.16 (dd, J=15.8, 9.0 Hz, 1H), 2.98 (dd, J=15.8, 6.7 Hz, 1H), 2.76 (s, 3H), 2.24 (s, 3H), 1.50 (d, J=14.6 Hz, 1H), 1.31 (s, 1H), 1.31-1.19 (m, J=6.4 Hz, 1H).

Example 535: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. Diisopropyl azodicarboxylate (0.40 mL, 2.04 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 500 mg, 1.24 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 423 mg, 1.76 mmol), and triphenylphosphine (482 mg, 1.84 mmol) in THF (14 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (770 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₃F₂N₅O₅S, 625.7; m/z found, 626.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=2.3 Hz, 1H), 8.11 (d, J=7.1 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.13-7.01 (m, 3H), 6.82 (d, J=7.2 Hz, 1H), 4.89 (t, J=7.8 Hz, 1H), 4.27 (s, 2H), 4.12-3.97 (m, 2H), 3.49 (s, 2H), 3.10 (dd, J=15.9, 7.3 Hz, 1H), 2.98 (dd, J=15.8, 8.5 Hz, 1H), 2.76 (s, 3H), 2.70 (d, J=4.0 Hz, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.98 (d, J=1.2 Hz, 2H), 1.19-1.13 (m, 3H), 0.53-0.42 (m, 2H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-348′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (770 mg, 1.23 mmol), 1 M aqueous NaOH solution (11.3 mL, 11.3 mmol) and THF (11.3 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (720 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₉F₂N₅O₅S, 597.2; m/z found, 598.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=2.4 Hz, 1H), 8.18 (d, J=7.1 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.17-7.05 (m, 3H), 6.91 (d, J=7.3 Hz, 1H), 5.31 (s, 1H), 4.96 (t, J=7.8 Hz, 1H), 4.31 (d, J=2.6 Hz, 2H), 3.51 (s, 2H), 3.43 (d, J=15.1 Hz, 1H), 3.18 (dd, J=15.9, 7.0 Hz, 1H), 3.06 (dd, J=15.9, 8.5 Hz, 1H), 2.77 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 1.12-0.99 (m, 1H), 1.05 (s, 1H), 0.46 (s, 2H).

Example 536: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 535, 720 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 65% CO₂, 35% EtOH) to afford two enantiomers. The first eluting isomer (349 mg) was designated (*S). MS (ESI): mass calcd. for C₂₉H₂₉F₂N₅O₅S, 597.2; m/z found, 598.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.25 (dd, J=2.4, 0.9 Hz, 1H), 8.21-8.04 (m, 2H), 7.28 (s, 1H), 7.18 (d, J=39.6 Hz, 1H), 7.14-7.05 (m, 2H), 7.05 (dd, J=7.9, 2.0 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 5.13 (s, 2H), 4.96 (t, J=7.8 Hz, 1H), 4.37 (d, J=14.5 Hz, 1H), 4.26 (d, J=14.5 Hz, 1H), 3.59 (d, J=15.8 Hz, 1H), 3.43 (d, J=15.1 Hz, 1H), 3.14 (dd, J=15.8, 7.2 Hz, 1H), 2.99 (dd, J=15.8, 8.5 Hz, 1H), 2.79 (s, 3H), 2.42 (s, 3H), 1.16-0.96 (m, 3H), 0.50 (dt, J=10.4, 6.1 Hz, 1H), 0.43 (dt, J=10.6, 6.1 Hz, 1H).

Example 537: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (339 mg) from the chiral separation described in Example 536 was designated (*R). MS (ESI): mass calcd. for C₂₉H₂₉F₂N₅O₅S, 597.2; m/z found, 598.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.25 (dd, J=2.4, 0.9 Hz, 1H), 8.21-8.03 (m, 2H), 7.28-7.12 (m, 1H), 7.12 (d, J=2.4 Hz, 2H), 7.05 (dd, J=7.8, 2.0 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 4.96 (t, J=7.8 Hz, 1H), 4.79 (s, 2H), 4.37 (d, J=14.6 Hz, 1H), 3.59 (d, J=15.7 Hz, 1H), 3.43 (s, 1H), 3.13 (dd, J=15.8, 7.2 Hz, 1H), 2.99 (dd, J=15.8, 8.4 Hz, 1H), 2.79 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 1.08-0.97 (m, 2H), 0.54-0.39 (m, 2H).

Example 538: (*S)-3-(4-Methyl-3-((7′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(4-methyl-3-((7′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DBAD (304 mg, 1.32 mmol) was added to a stirring mixture of ethyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 26, 350 mg, 0.83 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 423 mg, 1.76 mmol), and triphenylphosphine (349 mg, 1.33 mmol) in THF (12 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (530 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.2; m/z found, 644.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J=7.7 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.18-6.99 (m, 4H), 6.90 (d, J=7.3 Hz, 1H), 4.91 (dd, J=8.6, 7.2 Hz, 1H), 4.29 (s, 2H), 4.07 (dq, J=21.5, 7.1 Hz, 3H), 3.51 (q, J=15.1, 14.6 Hz, 2H), 3.12 (dd, J=15.9, 7.1 Hz, 1H), 2.99 (dd, J=15.9, 8.6 Hz, 1H), 2.80 (s, 3H), 2.27 (s, 3H), 2.02 (s, 1H), 1.27-1.08 (m, 6H), 0.64-0.49 (m, 2H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(4-methyl-348′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. A mixture containing ethyl (*S)-3-(4-methyl-3-((7′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (530 mg, 0.82 mmol), 1 M aqueous NaOH solution (7.6 mL, 7.6 mmol) and THF (7.6 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (483 mg, 95%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅O₅S, 615.6; m/z found, 616.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=7.8 Hz, 1H), 8.02 (d, J=7.1 Hz, 1H), 7.19-7.10 (m, 3H), 7.06 (dd, J=8.0, 1.9 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 5.30 (s, 1H), 4.97 (t, J=7.8 Hz, 1H), 4.35 (d, J=14.6 Hz, 1H), 4.26 (d, J=14.6 Hz, 1H), 3.57 (d, J=15.3 Hz, 1H), 3.49-3.39 (m, 1H), 3.18 (dd, J=16.1, 7.0 Hz, 1H), 3.04 (dd, J=16.1, 8.6 Hz, 1H), 2.81 (s, 3H), 2.55 (s, 3H), 2.29 (s, 3H), 1.15 (dt, J=12.2, 6.3 Hz, 1H), 1.02 (dt, J=11.7, 6.2 Hz, 1H), 0.56-0.50 (m, 1H), 0.48-0.40 (m, 1H).

Example 539: 3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(3-(((*R)-3-cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DBAD (453 mg, 1.97 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 500 mg, 1.24 mmol), (*R)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 87, 4022 mg, 1.52 mmol), and triphenylphosphine (521 mg, 1.99 mmol) in THF (18 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (750 mg, 93%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₃F₂N₇O₄S, 649.7; m/z found, 649.6 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, J=2.2 Hz, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.20-7.09 (m, 2H), 7.12-7.04 (m, 2H), 6.83 (dd, J=7.3, 6.2 Hz, 1H), 4.96-4.83 (m, 2H), 4.52 (dd, J=14.7, 6.0 Hz, 1H), 4.09 (dq, J=19.7, 7.2 Hz, 4H), 3.74-3.70 (m, 2H), 3.11 (dt, J=15.8, 6.9 Hz, 1H), 3.05-3.00 (m, 1H), 2.91-2.81 (m, 1H), 2.81 (d, J=2.1 Hz, 3H), 2.26 (d, J=6.0 Hz, 3H), 2.04 (s, 1H), 1.57-1.52 (m, 1H), 1.33-1.14 (m, 5H).

Step B: 3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(3-(((*R)-3-cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (750 mg, 1.15 mmol), 1 M aqueous NaOH solution (10.6 mL, 10.6 mmol) and THF (10.6 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (692 mg, 92%) as a white foam. MS (ESI): mass calcd. for C₃₀H₂₉F₂N₇O₄S, 621.2; m/z found, 621.6 [M]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=2.1 Hz, 1H), 8.26-8.15 (m, 1H), 7.23 (s, 1H), 7.20-7.08 (m, 3H), 6.93 (t, J=6.9 Hz, 1H), 5.32 (s, 2H), 5.00-4.82 (m, 2H), 4.53 (dd, J=14.8, 2.8 Hz, 1H), 4.12 (dd, J=14.8, 4.4 Hz, 1H), 3.72 (dt, J=8.8, 4.6 Hz, 2H), 3.51-3.33 (m, 1H), 3.19 (dt, J=15.9, 7.0 Hz, 1H), 3.10-3.04 (m, 1H), 2.96-2.83 (m, 1H), 2.76 (d, J=1.5 Hz, 3H), 2.27 (d, J=4.3 Hz, 3H), 2.12-2.06 (m, 1H), 1.98-1.90 (m, 1H), 1.88-1.68 (m, 1H), 1.59-1.51 (m, 1H).

Example 540: (*S)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((*R)-3-cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (Example 539, 692 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250×30 mm, Mobile phase: 50% CO₂, 50% EtOH) to provide two diastereomers. The first eluting diastereomer (330 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₂₉F₂N₇O₄S, 621.2; m/z found, 621.6 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (d, J=2.1 Hz, 1H), 8.24 (d, J=2.2 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.13-7.07 (m, 2H), 6.86 (d, J=7.3 Hz, 1H), 4.94 (dd, J=8.9, 6.7 Hz, 1H), 4.92-4.84 (m, 1H), 4.53 (d, J=14.7 Hz, 1H), 4.32 (s, 2H), 4.10 (d, J=14.7 Hz, 1H), 3.71 (dd, J=8.5, 4.8 Hz, 2H), 3.36 (dd, J=13.1, 3.6 Hz, 1H), 3.15 (dd, J=15.9, 6.7 Hz, 1H), 3.04 (dd, J=15.9, 9.0 Hz, 1H), 2.87 (q, J=13.0, 12.4 Hz, 1H), 2.78 (s, 3H), 2.27 (s, 3H), 2.14-2.02 (m, 1H), 1.92-1.88 (m, 1H), 1.79-1.69 (m, 1H), 1.58-1.50 (m, 1H).

Example 541: (*R)-3-(3-(((*R)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting diastereomer (330 mg) from the chiral separation described in Example 540 was designated (*R). MS (ESI): mass calcd. for C₃₀H₂₉F₂N₇O₄S, 621.2; m/z found, 621.6 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d, J=2.2 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.18-7.13 (m, 2H), 7.13-7.07 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 4.98-4.86 (m, 2H), 4.52 (d, J=14.9 Hz, 1H), 4.34 (s, 3H), 4.11 (d, J=14.9 Hz, 1H), 3.78-3.69 (m, 2H), 3.45 (dd, J=13.1, 3.6 Hz, 1H), 3.17 (dd, J=16.0, 6.6 Hz, 1H), 3.05 (dd, J=15.9, 9.0 Hz, 1H), 2.88 (t, J=12.5 Hz, 1H), 2.78 (s, 3H), 2.26 (s, 3H), 2.14-2.03 (m, 1H), 1.86-1.76 (m, 1H), 1.60-1.53 (m, 1H).

Example 542: 3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(3-(((*S)-3-cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. DBAD (453 mg, 1.97 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, Step C, 500 mg, 1.24 mmol), (*S)-6,7,7a,8,9,10-hexahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepine-3-carbonitrile 5,5-dioxide (Intermediate 88, 402 mg, 1.52 mmol), and triphenylphosphine (521 mg, 1.99 mmol) in THF (18 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (790 mg, 98%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₃F₂N₇O₄S, 649.7; m/z found, 650.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.2 Hz, 1H), 8.22 (t, J=1.9 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 7.17-7.02 (m, 3H), 6.83 (t, J=7.3 Hz, 1H), 4.95-4.81 (m, 2H), 4.51 (dd, J=14.6, 5.7 Hz, 1H), 4.16-3.98 (m, 4H), 3.77-2.98 (m, 2H), 3.11 (dt, J=15.8, 6.8 Hz, 1H), 3.03-2.97 (m, 1H), 2.86-2.74 (m, 4H), 2.25 (d, J=5.7 Hz, 3H), 2.14-2.00 (m, 1H), 2.03 (s, 1H), 1.58-1.50 (m, 1H), 1.24 (t, J=7.1 Hz, 2H), 1.16 (td, J=7.1, 2.2 Hz, 3H).

Step B: 3-(3-(((*S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(3-(((*S)-3-cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (790 mg, 1.22 mmol), 1 M aqueous NaOH solution (11 mL, 11 mmol) and THF (11 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (750 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₀H₂₉F₂N₇O₄S, 621.2; m/z found, 621.6 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47 (d, J=2.2 Hz, 2H), 8.21 (d, J=2.1 Hz, 2H), 8.16 (d, J=7.2 Hz, 1H), 7.19-7.03 (m, 3H), 6.90 (t, J=7.7 Hz, 2H), 4.97-4.81 (m, 2H), 4.51 (dd, J=14.8, 3.4 Hz, 1H), 4.10 (dd, J=14.8, 5.2 Hz, 1H), 3.72-3.68 (m, 1H), 3.49-3.39 (m, 1H), 3.19-3.15 (m, 1H), 3.09-3.03 (m, 1H), 2.87 (q, J=12.3 Hz, 1H), 2.74 (d, J=1.9 Hz, 3H), 2.25 (d, J=5.6 Hz, 3H), 2.09-2.03 (m, 1H), 1.95-1.90 (m, 1H), 1.86-1.67 (m, 1H), 1.58-1.53 (m, 1H).

Example 543: (*S)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-(((*S)-3-cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 542, 730 mg) was separated by chiral SFC (stationary phase: Chiralpak IA 5 μm 250×20 mm, Mobile phase: 40% CO₂, 60% MeOH (0.6% formic acid)) to provide two diastereomers. The first eluting diastereomer (367 mg) was designated (*S). MS (ESI): mass calcd. for C₃₀H₂₉F₂N₇O₄S, 621.2; m/z found, 622.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (d, J=2.2 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.18-7.12 (m, 3H), 7.13-7.07 (m, 1H), 6.89 (d, J=7.2 Hz, 1H), 4.98-4.86 (m, 2H), 4.52 (d, J=14.9 Hz, 1H), 4.11 (d, J=14.9 Hz, 1H), 3.79-3.69 (m, 2H), 3.52-3.41 (m, 1H), 3.18 (dd, J=16.0, 6.5 Hz, 1H), 3.06 (dd, J=16.0, 9.0 Hz, 1H), 2.88 (t, J=12.5 Hz, 1H), 2.78 (s, 3H), 2.26 (s, 3H), 2.09 (dt, J=11.3, 5.8 Hz, 1H), 2.00-1.93 (m, 1H), 1.62-1.57 (m, 1H), 1.29-1.21 (m, 1H).

Example 544: (*R)-3-(3-(((S)-3-Cyano-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting diastereomer (365 mg) from the chiral separation described in Example 543 was designated (*R). MS (ESI): mass calcd. for C₃₀H₂₉F₂N₇O₄S, 621.2; m/z found, 622.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=6.9 Hz, 1H), 7.28 (s, 1H), 7.18-7.07 (m, 3H), 6.99 (s, 1H), 6.87 (d, J=7.2 Hz, 1H), 4.94 (s, 1H), 4.88 (s, 1H), 4.52 (d, J=14.8 Hz, 1H), 4.10 (d, J=14.8 Hz, 1H), 3.71 (s, 1H), 3.37 (d, J=13.0 Hz, 1H), 3.17-3.11 (m, 1H), 3.03 (d, J=16.9 Hz, 1H), 2.87 (d, J=12.6 Hz, 1H), 2.78 (s, 3H), 2.27 (s, 3H), 2.08 (s, 1H), 1.91 (s, 1H), 1.75 (s, 1H), 1.21 (s, 1H).

Example 545: (2*S,3*R)-2-Methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (2*S,3*R)-2-methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.06 mL, 0.31 mmol) was added to a stirring mixture of methyl (2*S,3*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 175, 80 mg, 0.19 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 65 mg, 0.27 mmol) and triphenylphosphine (74 mg, 0.28 mmol) in THF (2.2 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (100 mg, 82%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.7; m/z found, 644.3 [M+H]⁺.

Step B: (2*S,3*R)-2-Methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl (2*S,3*R)-2-methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (100 mg, 0.16 mmol), 1 M aqueous NaOH solution (1.4 mL, 1.4 mmol), THF (1.4 mL) and ethanol (0.1 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (97 mg, 99%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.7; m/z found, 630.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.24 (dd, J=2.4, 0.8 Hz, 1H), 8.10-8.02 (m, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.17-7.10 (m, 2H), 6.51 (s, 1H), 4.46 (d, J=11.4 Hz, 1H), 4.32 (s, 2H), 3.54 (d, J=15.1 Hz, 1H), 3.47 (d, J=15.4 Hz, 1H), 3.35 (dq, J=11.3, 6.8 Hz, 1H), 2.73 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H), 1.23 (d, J=6.8 Hz, 3H), 1.20-1.11 (m, 2H), 0.52 (s, 2H).

Example 546: (2*R,3*R)-2-Methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (2*R,3*R)-2-methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.06 mL, 0.31 mmol) was added to a stirring mixture of methyl (2*R,3*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 176, 50 mg, 0.12 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 40 mg, 0.17 mmol) and triphenylphosphine (46 mg, 0.18 mmol) in THF (2 mL) at room temperature. After 1 hour, ethyl acetate and water were added. The biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (70 mg, 92%) as a white foam. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₅S, 643.7; m/z found, 644.2 [M+H]⁺.

Step B: (2*R,3*R)-2-Methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl (2*R,3*R)-2-methyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (70 mg, 0.11 mmol), 1 M aqueous NaOH solution (1.0 mL, 1.4 mmol) and THF (1.0 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (47 mg, 69%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.7; m/z found, 630.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 11.13 (s, 1H), 8.24 (dd, J=2.4, 0.9 Hz, 1H), 8.07 (dd, J=2.4, 0.8 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.12-7.02 (m, 2H), 6.93 (d, J=7.3 Hz, 1H), 4.63 (d, J=11.5 Hz, 1H), 4.35-4.24 (m, 2H), 3.61 (d, J=15.5 Hz, 1H), 3.47 (d, J=15.2 Hz, 1H), 3.35 (dq, J=13.6, 6.9 Hz, 1H), 2.85 (s, 3H), 2.41 (s, 3H), 2.22 (s, 3H), 1.19-1.13 (m, 5H), 0.65-0.56 (m, 2H).

Example 547: 3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide

To a solution of 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 289, 100 mg, 0.16 mmol) in DCM (3 mL) was added sequentially ammonium hydroxide (17 mg, 0.48 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (93 mg, 0.48 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between EtOAc and water (25 mL each). The aqueous phase was extracted with EtOAc (2×25 mL). These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (90 mg, 90%) as a white foam. MS (ESI): mass calcd. for C₂₀H₃₂F₃N₇O₃S, 627.2; m/z found, 628.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (dd, J=4.6, 1.8 Hz, 1H), 8.00-7.89 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 6.95 (dd, J=7.9, 2.0 Hz, 1H), 6.83-6.73 (m, 2H), 5.65 (s, 1H), 5.31 (s, 1H), 5.23 (s, 1H), 4.96 (t, J=7.6 Hz, 1H), 4.50 (dq, J=14.0, 4.7 Hz, 1H), 4.41 (d, J=15.3 Hz, 1H), 4.25 (dt, J=13.4, 4.9 Hz, 1H), 4.16 (d, J=15.3 Hz, 1H), 3.29 (dd, J=13.2, 3.8 Hz, 1H), 3.24-3.15 (m, 2H), 2.99 (dd, J=15.0, 7.7 Hz, 1H), 2.83-2.75 (m, 4H), 2.17 (s, 3H), 1.77-1.61 (m, 2H), 1.56-1.38 (m, 3H).

Example 548: (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide

The mixture of 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide (Example 547, 85 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% iPOH (0.3% iPrNH₂)) to provide two diastereomers. The first eluting diastereomer (32 mg, 32%) was designated (*S). MS (ESI): mass calcd. for C₂₀H₃₂F₃N₇O₃S, 627.2; m/z found, 628.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ ¹H NMR (500 MHz, Chloroform-d) δ 8.23 (dd, J=4.7, 1.8 Hz, 1H), 8.00-7.89 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.95 (dd, J=7.8, 2.0 Hz, 1H), 6.83-6.73 (m, 2H), 5.65 (s, 1H), 5.31 (s, 1H), 5.23 (s, 1H), 4.96 (t, J=7.6 Hz, 1H), 4.55-4.46 (m, 1H), 4.41 (d, J=15.3 Hz, 1H), 4.25 (dt, J=13.3, 4.9 Hz, 1H), 4.16 (d, J=15.3 Hz, 1H), 3.29 (dd, J=13.3, 3.8 Hz, 1H), 3.24-3.15 (m, 2H), 2.99 (dd, J=15.0, 7.7 Hz, 1H), 2.87 (s, 3H), 2.17 (s, 3H), 1.75-1.55 (m, 2H), 1.56-1.43 (m, 1H), 1.46-1.39 (m, 1H), 0.84-0.78 (m, 2H).

Example 549: (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide

The mixture of 3-(3-(((*S)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanamide (Example 547, 85 mg) was separated by chiral SFC (stationary phase: Chiralpak AD-H 5 μm 250*30 mm, Mobile phase: 50% CO₂, 50% iPOH (0.3% iPrNH₂)) to provide two diastereomers. The second eluting diastereomer (36 mg, 36%) was designated (*R). MS (ESI): mass calcd. for C₂₀H₃₂F₃N₇O₃S, 627.2; m/z found, 628.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ ¹H NMR (500 MHz, Chloroform-d) 6 ¹H NMR (500 MHz, Chloroform-d) δ 8.32 (dd, J=4.6, 1.9 Hz, 1H), 8.09-7.99 (m, 2H), 7.27 (d, J=1.9 Hz, 1H), 7.16-7.06 (m, 2H), 6.93-6.82 (m, 2H), 5.75 (s, 1H), 5.44 (s, 1H), 5.03 (t, J=7.6 Hz, 1H), 4.51-4.58 (m, 1H), 4.48 (d, J=15.2 Hz, 1H), 4.35-4.22 (m, 2H), 3.33-3.20 (m, 3H), 3.05 (dd, J=15.0, 7.3 Hz, 1H), 2.93-2.81 (m, 1H), 2.87 (s, 3H), 2.27 (s, 3H), 1.78-1.63 (m, 1H), 1.59-1.37 (m, 2H), 0.90 (t, J=6.9 Hz, 3H).

Example 551: 3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl 3-(3-((8′-chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Di-tert-butyl azodicarboxylate (1.12 g, 4.87 mmol) was added to a stirring mixture of ethyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (Example 28, step C, 1.21 g, 3.00 mmol), 8′-chloro-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 96, 900 mg, 3.45 mmol), and triphenylphosphine (1.28 g, 4.89 mmol) in THF (45 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (1.80 g, 93%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀ClF₂N₅O₅S, 645.2; m/z found, 646.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 8.18 (d, J=7.2 Hz, 1H), 7.18-7.06 (m, 3H), 6.85 (d, J=7.2 Hz, 1H), 4.93 (t, J=7.9 Hz, 1H), 4.34 (s, 2H), 4.16-4.07 (m, 2H), 4.07 (d, J=7.1 Hz, 1H), 3.54 (s, 2H), 3.14 (dd, J=15.9, 7.3 Hz, 1H), 3.02 (dd, J=15.9, 8.5 Hz, 1H), 2.80 (s, 3H), 2.30 (s, 2H), 2.04 (s, 1H), 1.26 (t, J=7.1 Hz, 1H), 1.25-1.14 (m, 4H), 0.62-0.52 (m, 2H).

Step B: Ethyl 3-(3-((8′-cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A mixture containing ethyl 3-(3-((8′-chloro-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (1.0 g, 1.55 mmol), zinc cyanide (482 mg, 4.11 mmol), zinc powder (677 mg, 10.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (318 mg, 0.35 mmol), dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine (421 mg, 0.88 mmol) and DMA (51.3 mL) was degassed by bubbling nitrogen through the reaction mixture for 15 minutes. The reaction mixture was then heated at 120° C. overnight. Cooled and filtered the reaction mixture, rinsed with ethyl acetate. The filtrate was washed with aqueous sodium bicarbonate and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (600 mg, 61%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₁F₂N₆O₅S, 636.2; m/z found, 637.2 [M]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.71 (d, J=2.3 Hz, 1H), 8.55 (d, J=2.3 Hz, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.14-7.06 (m, 2H), 6.83 (d, J=7.3 Hz, 1H), 4.93 (t, J=7.9 Hz, 1H), 4.37 (s, 2H), 4.16-4.03 (m, 2H), 3.54 (s, 2H), 3.13 (dd, J=15.8, 7.4 Hz, 1H), 3.05-2.96 (m, 1H), 2.82-2.78 (m, 3H), 2.30 (s, 3H), 2.07 (d, J=19.1 Hz, 2H), 1.33-1.03 (m, 4H), 0.73-0.64 (m, 2H).

Step C: 3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. A mixture containing ethyl 3-(3-((8′-cyano-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (600 mg, 0.94 mmol), 1 M aqueous NaOH solution (2.6 mL, 2.6 mmol), THF (5.3 mL) and ethanol (0.2 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (355 mg, 60%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₆F₂N₆O₅S, 626.2; m/z found, 627.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ¹H NMR (500 MHz, Chloroform-d) δ 7.91 (t, J=5.7 Hz, 1H), 7.85-7.76 (m, 2H), 7.09-7.04 (m, 1H), 6.80-6.68 (m, 3H), 4.70-4.62 (m, 1H), 4.49-4.36 (m, 2H), 4.17 (s, 4H), 3.22 (d, J=3.7 Hz, 2H), 3.20-3.09 (m, 1H), 2.93-2.84 (m, 1H), 2.79-2.71 (m, 1H), 2.51 (d, J=5.1 Hz, 2H), 1.96 (d, J=4.6 Hz, 2H), 0.41-0.31 (m, 2H), 0.00 (d, J=3.7 Hz, 2H).

Example 552: (*S)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((8′-carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 551, 344 mg) was separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 45% CO₂, 55% EtOH) to provide two diastereomers. The first eluting diastereomer (156 mg, 26%) was designated (*S). MS (ESI): mass calcd. for C₂₉H₂₆F₂N₆O₅S, 626.2; m/z found, 627.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ¹H NMR (500 MHz, Chloroform-d) δ 8.18 (d, J=6.5 Hz, 1H), 8.11 (q, J=2.5 Hz, 1H), 7.99 (q, J=2.8 Hz, 1H), 7.37-7.30 (m, 3H), 7.22-7.17 (m, 1H), 7.12-6.93 (m, 4H), 4.75-4.62 (m, 1H), 3.49 (d, J=3.9 Hz, 2H), 3.44-3.31 (m, 2H), 3.14-3.07 (m, 1H), 2.99 (s, 1H), 2.81-2.73 (m, 3H), 2.30-2.17 (m, 3H), 0.63 (t, J=4.0 Hz, 2H), 0.28 (d, J=4.1 Hz, 2H).

Example 553: (*R)-3-(3-((8′-Carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of 3-(3-((8′-carbamoyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (Example 551, 344 mg) was separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 45% CO₂, 55% EtOH) to provide two diastereomers. The second eluting diastereomer (158 mg, 27%) was designated (*R). MS (ESI): mass calcd. for C₂₉H₂₆F₂N₆O₅S, 626.2; m/z found, 627.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ ¹H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=7.0 Hz, 1H), 8.10 (q, J=3.3, 2.9 Hz, 1H), 8.01 (q, J=3.8, 3.3 Hz, 1H), 7.39-7.29 (m, 3H), 7.07-6.95 (m, 3H), 4.76-4.63 (m, 2H), 3.49 (d, J=4.3 Hz, 2H), 3.42-3.30 (m, 3H), 3.12 (dd, J=15.7, 6.9 Hz, 1H), 2.99 (dd, J=15.6, 8.4 Hz, 1H), 2.81-2.72 (m, 3H), 2.26-2.18 (m, 3H), 1.28-1.17 (m, 2H), 0.63 (s, 2H), 0.28 (d, J=5.3 Hz, 2H).

Example 554: (2S,3*R)-3-(3-(Trifluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid

Step A: Methyl (2S,3*R))-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Diisopropyl azodicarboxylate (0.13 mL, 0.66 mmol) was added to a stirring mixture of methyl (2*S,3*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 175, 168 mg, 0.40 mmol), 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 136 mg, 0.60 mmol), and triphenylphosphine (155 mg, 0.60 mmol) in THF (5 mL) at room temperature. After 1 hour, ethyl acetate and water were added and the biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined and washed sequentially with water and brine solution. The organic fractions were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to provide the title compound (240 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₅S, 629.2; m/z found, 630.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (dd, J=4.8, 1.9 Hz, 1H), 8.29 (dd, J=7.7, 1.9 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.33 (dd, J=7.6, 4.9 Hz, 1H), 7.27-7.09 (m, 4H), 4.47 (d, J=11.5 Hz, 1H), 4.38-4.27 (m, 2H), 3.59 (d, J=15.3 Hz, 1H), 3.52 (s, 3H), 3.50-3.43 (m, 1H), 3.35 (dq, J=11.4, 6.8 Hz, 1H), 2.78 (s, 2H), 2.26 (s, 3H), 1.28-1.15 (m, 6H), 0.62-0.55 (m, 2H).

Step B: (2S,3*R)-3-(3-(Trifluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid. A mixture containing methyl (2S,3*R)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2-methyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (240 mg, 0.38 mmol), 1 M aqueous NaOH solution (3.5 mL, 3.5 mmol), ethanol (0.10 mL) and THF (3.5 mL) was stirred at room temperature overnight. 1 M Aqueous HCl solution was added until the pH was 3-4. Ethyl acetate was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed sequentially with water and brine solution, dried over Na₂SO₄, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (225 mg, 96%) as a white foam. MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅O₅S, 615.2; m/z found, 616.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.21 (s, 2H), 8.45 (dd, J=4.9, 2.0 Hz, 1H), 8.30 (dd, J=7.6, 2.0 Hz, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.34 (dd, J=7.6, 4.9 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20-7.09 (m, 3H), 4.46 (d, J=11.4 Hz, 1H), 4.38-4.26 (m, 1H), 3.57 (d, J=15.2 Hz, 1H), 3.48 (d, J=15.0 Hz, 1H), 3.36 (dq, J=11.3, 6.8 Hz, 1H), 2.70 (s, 3H), 2.27 (s, 3H), 1.17 (q, J=5.7, 4.4 Hz, 3H), 0.58-0.52 (m, 2H), 0.00 (s, 2H).

Example 555: (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

Step A: Methyl (R/S)-3-(641′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. A solution of methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (Intermediate 168, 150 mg, 0.38 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 126 mg, 0.47 mmol), and triphenylphosphine (158 mg, 0.60 mmol) in THF (4 mL) and DMF (4 ml) was stirred at room temperature for 5 minutes. DBAD (139 mg, 0.61 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (150 mg, 61%) as a white foam. MS (ESI): mass calcd. for C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.2 [M+H]⁺.

Step B: (R/S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid. Lithium hydroxide (111 mg, 4.62 mmol) was added to a solution of methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (150 mg, 0.23 mmol) in MeOH (3 mL), THF (3 mL) and water (3 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was approximately 6. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography(eluent: 0-10% MeOH/DCM) to afford the title compound (80 mg, 55%) as a white foam. MS (ESI): mass calcd. for C₃₂H₃₈N₆O₆S, 634.3; m/z found, 635.2 [M+H]⁺. 1 H NMR (500 MHz, CDCl₃) δ d 11.52 (s, 1H), 8.59 (dd, J=4.9, 2.0 Hz, 1H), 8.25 (dd, J=7.7, 1.9 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.41-7.33 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 4.89 (s, 1H), 4.73 (d, J=2.6 Hz, 2H), 4.64 (q, J=7.3 Hz, 2H), 4.07 (t, J=11.6 Hz, 2H), 4.00-3.90 (m, 2H), 3.78 (td, J=11.9, 4.3 Hz, 2H), 2.98 (s, 3H), 2.39 (s, 3H), 1.88-1.75 (m, 2H), 1.70 (t, J=11.1 Hz, 2H), 1.46 (s, 3H), 1.35 (s, 6H).

Step C: (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid. The mixture of (R/S)-3-(6-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid (80 mg) was separated by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 70% CO₂, 30% EtOH) to afford two diastereomers. The first eluting isomer (25 mg, 17%) was designated (*S): MS: mass calcd. for C₃₂H₃₈N₆O₆S, 634.3; m/z found, 635.2 [M+H]⁺. 1 H NMR (600 MHz, CDCl₃) δ 8.45 (dd, J=4.8, 2.0 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.25-7.17 (m, 2H), 6.97 (d, J=7.9 Hz, 1H), 5.22 (s, 1H), 4.83 (s, 1H), 4.60 (s, 2H), 4.60 (t, J=16.4 Hz, 0H), 4.58-4.48 (m, 2H), 4.11-3.95 (m, 2H), 3.73-3.62 (m, 4H), 2.92 (s, 3H), 2.29 (s, 3H), 1.68 (s, 2H), 1.68-1.60 (m, 2H), 1.50 (t, J=7.3 Hz, 3H), 1.30 (d, J=7.7 Hz, 6H).

Example 556: (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid

The second eluting isomer (28 mg, 19%) from the chiral separation described in Example 555 was designated (*R): MS: mass calcd. for C₃₂H₃₈N₆O₆S, 634.3; m/z found, 635.2 [M+H]⁺. 1 H NMR (600 MHz, CDCl₃) δ 8.46 (dd, J=4.9, 2.0 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.26-7.18 (m, 2H), 6.97 (d, J=7.9 Hz, 1H), 5.22 (s, 1H), 4.83 (s, 1H), 4.60 (s, 2H), 4.58-4.49 (m, 2H), 4.11-3.95 (m, 2H), 3.71 (s, 3H), 3.69-3.63 (m, 1H), 2.92 (s, 3H), 2.29 (s, 3H), 1.75-1.57 (m, 4H), 1.50 (t, J=7.3 Hz, 3H), 1.30 (d, J=13.7 Hz, 6H).

Example 557: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl (R/S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (Intermediate 168, 170 mg, 0.43 mmol), 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 150 mg, 0.53 mmol), and triphenylphosphine (179 mg, 0.68 mmol) in THF (5 mL) and DMF (5 ml) was stirred at room temperature for 5 minutes. DBAD (158 mg, 0.69 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (250 mg, 88%) as a white foam. MS (ESI): mass calcd. for C₃₄H₄₂N₆O₆S, 662.3; m/z found, 663.2 [M+H]⁺.

Step B: (R/S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. Lithium hydroxide (181 mg, 7.54 mmol) was added to a solution of methyl (R/S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (250 mg, 0.38 mmol) in MeOH (5 mL), THF (5 mL) and water (5 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was approximately 6. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to afford the title compound (220 mg, 90%) as a white foam. MS (ESI): mass calcd. for C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺.

Step C: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. The mixture of (R/S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-64(8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid (220 mg) was separated by chiral SFC ((Stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 70% CO₂, 30% EtOH) to afford two diastereomers. The first eluting isomer (54 mg, 22%) was designated (*S), which was further purified by reverse phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, Mobile phase: Gradient from 65% HCOONH₄ 0.6 g/L pH=3.5, 35% ACN to 25% HCOONH₄ 0.6 g/L pH=3.5, 75% ACN) followed by another reverse phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, Mobile phase: Gradient from 75% NH₄HCO₃ 0.2%, 25% ACN to 35% NH₄HCO₃ 0.2%, 65% ACN) to afford the title compound (22 mg, 9%): MS: mass calcd. for C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.33 (dd, J=2.4, 0.9 Hz, 1H), 8.06-8.02 (m, 1H), 7.49 (dd, J=15.0, 8.4 Hz, 2H), 7.28 (d, J=9.1 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 4.87 (s, 1H), 4.68 (s, 2H), 4.66-4.56 (m, 2H), 4.11-4.04 (m, 2H), 3.79-3.68 (m, 4H), 3.01 (s, 3H), 2.41 (d, J=29.1 Hz, 6H), 1.82-1.73 (m, 2H), 1.76-1.69 (m, 2H), 1.58 (t, J=7.3 Hz, 3H), 1.41 (s, 3H), 1.36 (s, 3H).

Example 558: (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (54 mg, 22%) from the chiral separation described in Example 557 was designated (*R) which was further purified by reverse phase (Stationary phase: YMC-actus Triart C18 10 μm 30*150 mm, Mobile phase: Gradient from 65% HCOONH₄ 0.6 g/L pH=3.5, 35% ACN to 25% HCOONH₄ 0.6 g/L pH=3.5, 75% ACN) to afford the title compound (43 mg, 18%): MS: mass calcd. for C₃₃H₄₀N₆O₆S, 648.3; m/z found, 649.3 [M+H]⁺. 1 H NMR (600 MHz, CDCl₃) δ 8.32 (dd, J=2.4, 0.9 Hz, 1H), 8.06-8.02 (m, 1H), 7.48 (dd, J=22.4, 8.4 Hz, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 4.89 (s, 1H), 4.67 (s, 2H), 4.61 (q, J=7.3 Hz, 2H), 4.13-4.04 (m, 2H), 3.80-3.68 (m, 4H), 3.00 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H), 1.80-1.64 (m, 4H), 1.57 (d, J=14.7 Hz, 3H), 1.40 (s, 3H), 1.36 (s, 3H).

Example 559: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 49, 2.0 g, 4.8 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 1.5 g, 6.0 mmol), and triphenylphosphine (1.8 g, 7.1 mmol) in THF (133 mL) and DMF (13 ml) was stirred at room temperature for 5 minutes. DBAD (1.9 g, 7.9 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (2.9 g, 95% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₂N₅O₅S, 639.2; m/z found, 640.3 [M+H]⁺.

Step B: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Lithium hydroxide (0.83 g, 19.7 mmol) was added to a solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (2.9 g, 3.9 mmol) in MeOH (25 mL) and water (17 mL). The reaction was stirred at 70° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 3-4. EtOAc was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (2.5 g, 99% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₂N₅O₅S, 625.2; m/z found, 626.2 [M+H]⁺.

Example 560: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid (Example 559, 2.5 g) was separated by chiral SFC (stationary phase: Chiralpak IC, 5 μm, 2×25 cm, Mobile phase: 20% MeOH (0.1% DEA), 80% CO₂) to afford two enantiomers. The first eluting isomer (1.17 g, 47%) was designated (*S): MS: mass calcd. for C₃₁H₃₃F₂N₅O₅S, 625.2; m/z found, 626.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 8.26-8.22 (m, 1H), 8.11-8.04 (m, 2H), 7.26-7.23 (m, 1H), 7.32-7.09 (m, 1H), 7.16-7.12 (m, 1H), 7.09-7.05 (m, 1H), 7.04-6.99 (m, 1H), 4.76 (s, 1H), 4.32-4.20 (m, 2H), 3.57-3.40 (m, 2H), 2.63 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H), 1.27 (s, 3H), 1.21 (s, 3H), 1.18-1.09 (m, 2H), 0.49-0.37 (m, 2H).

Example 561: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (1.19 g, 48%) from the chiral separation described in Example 560 was designated (*R): MS: mass calcd. for C₃₁H₃₃F₂N₅O₅S, 625.2; m/z found, 626.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 8.28-8.22 (m, 1H), 8.13-8.05 (m, 2H), 7.28-7.24 (m, 1H), 7.34-7.10 (m, 1H), 7.19-7.13 (m, 1H), 7.10-7.06 (m, 1H), 7.03-6.99 (m, 1H), 4.78 (s, 1H), 4.36-4.19 (m, 2H), 3.54-3.43 (m, 2H), 2.64 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 1.18-1.11 (m, 2H), 0.50-0.37 (m, 2H).

Example 562: (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*S)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of ethyl (*S)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 173, 200 mg, 0.47 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 158 mg, 0.58 mmol), and triphenylphosphine (198 mg, 0.75 mmol) in THF (5 mL) was stirred at room temperature for 5 minutes. DBAD (175 mg, 0.75 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (300 mg, 94% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.50 (dd, J=4.9, 2.0 Hz, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.16 (dd, J=7.6, 2.0 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.29-7.23 (m, 1H), 6.94 (d, J=7.3 Hz, 1H), 4.99 (t, J=7.8 Hz, 1H), 4.47 (s, 2H), 4.13-3.99 (m, 4H), 3.64 (dt, J=21.3, 10.6 Hz, 3H), 3.44 (s, 2H), 3.17 (dd, J=16.0, 7.3 Hz, 1H), 3.08 (dd, J=16.1, 8.5 Hz, 1H), 2.84 (d, J=0.7 Hz, 3H), 2.43 (s, 3H), 1.75-1.64 (m, 1H), 1.66-1.48 (m, 2H), 1.17 (t, J=7.1 Hz, 3H).

Step B: (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Sodium hydroxide solution(1 M, 4.1 mL, 4.1 mmol) was added to a solution of ethyl (*S)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (300 mg, 0.45 mmol) in THF (5 mL). The reaction was stirred at room temperature overnight. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (280 mg, 97% yield). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₆S, 646.2; m/z found, 647.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (dd, J=4.9, 2.0 Hz, 1H), 8.40 (d, J=2.1 Hz, 1H), 8.13 (dd, J=7.6, 2.0 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.88 (s, 2H), 7.68 (d, J=2.2 Hz, 1H), 7.26 (dd, J=7.6, 4.9 Hz, 1H), 6.99 (d, J=7.3 Hz, 1H), 5.01 (t, J=7.7 Hz, 1H), 4.48 (s, 2H), 3.99 (tt, J=9.2, 3.4 Hz, 2H), 3.60 (s, 2H), 3.64-3.56 (m, 1H), 3.52 (s, 1H), 3.44 (s, 1H), 3.19 (dd, J=16.0, 7.8 Hz, 1H), 3.08 (dd, J=16.0, 7.6 Hz, 1H), 2.78 (s, 3H), 2.41 (s, 3H), 1.55-1.50 (m, 2H).

Example 563: (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

Step A: Ethyl (*S)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate. A solution of A solution of ethyl (*S)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 173, 250 mg, 0.59 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 175 mg, 0.73 mmol), and triphenylphosphine (247 mg, 0.94 mmol) in THF (6 mL) was stirred at room temperature for 5 minutes. DBAD (218 mg, 0.95 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (380 mg, 99% yield). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J=2.3 Hz, 1H), 8.22 (dd, J=2.4, 0.9 Hz, 1H), 8.06-7.99 (m, 2H), 7.52 (d, J=2.3 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 4.93 (t, J=7.8 Hz, 1H), 4.29 (s, 2H), 4.09-4.01 (m, 2H), 3.51 (d, J=15.4 Hz, 1H), 3.41 (s, 1H), 3.13 (dd, J=16.1, 7.4 Hz, 1H), 3.03 (dd, J=16.1, 8.3 Hz, 1H), 2.79 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H), 1.25-1.10 (m, 5H), 0.65-0.56 (m, 2H).

Step B: (*S)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid. Sodium hydroxide solution(1 M, 5.4 mL, 5.4 mmol) was added to a solution of ethyl (*S)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (380 mg, 0.59 mmol) in THF (5 mL). The reaction was stirred at room temperature overnight. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (359 mg, 99% yield). MS (ESI): mass calcd. for C₂₄H₂₇F₃N₆O₅S, 616.2; m/z found, 617.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=2.2 Hz, 1H), 8.24 (dd, J=2.4, 0.9 Hz, 2H), 8.10-8.01 (m, 2H), 7.64 (d, J=2.2 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 5.00 (t, J=7.7 Hz, 1H), 4.31 (s, 2H), 3.56-3.48 (m, 1H), 3.46 (s, 1H), 3.17 (dd, J=16.1, 7.8 Hz, 1H), 3.06 (dd, J=16.0, 7.7 Hz, 1H), 2.79 (s, 3H), 2.42 (d, J=19.1 Hz, 6H), 1.14 (s, 2H), 0.58 (q, J=5.7, 4.6 Hz, 2H).

Example 564: (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Ethyl (*R)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of ethyl (*R)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 172, 205 mg, 0.49 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 162 mg, 0.60 mmol), and triphenylphosphine (203 mg, 0.77 mmol) in THF (5 mL) was stirred at room temperature for 5 minutes. DBAD (179 mg, 0.78 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (320 mg, 98% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (dd, J=4.9, 2.0 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.12 (dd, J=7.6, 1.9 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.23 (dd, J=7.6, 4.9 Hz, 1H), 6.93 (d, J=7.3 Hz, 1H), 4.96 (t, J=7.8 Hz, 1H), 4.45 (s, 1H), 4.09-3.94 (m, 2H), 3.63-3.56 (m, 3H), 3.47 (s, 1H), 3.15 (dd, J=16.1, 7.3 Hz, 1H), 3.06 (dd, J=16.1, 8.5 Hz, 1H), 2.80 (s, 3H), 2.45 (s, 1H), 2.39 (s, 3H), 1.98 (s, 1H), 1.70-1.60 (m, 2H), 1.58-1.50 (m, 2H), 1.19 (t, J=7.2 Hz, 1H), 1.13 (t, J=7.1 Hz, 3H).

Step B: (*R)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Sodium hydroxide solution(1 M, 4.4 mL, 4.4 mmol) was added to a solution of ethyl (*R)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (320 mg, 0.47 mmol) in THF (5 mL). The reaction was stirred at room temperature overnight. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (300 mg, 98% yield). MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆O₆S, 646.2; m/z found, 647.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (dt, J=3.5, 1.8 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.16 (dt, J=7.7, 2.1 Hz, 1H), 8.09 (d, J=7.1 Hz, 1H), 7.67 (d, J=2.3 Hz, 1H), 7.31-7.24 (m, 1H), 6.99 (d, J=7.3 Hz, 1H), 6.50 (s, 2H), 4.49 (s, 1H), 4.02 (dt, J=16.6, 7.7 Hz, 2H), 3.68-3.59 (m, 3H), 3.56-3.44 (m, 2H), 3.20 (dd, J=16.0, 8.2 Hz, 1H), 3.08 (dd, J=16.0, 7.4 Hz, 1H), 2.80 (d, J=4.5 Hz, 3H), 2.45-2.37 (m, 3H), 1.65-1.46 (m, 4H).

Example 565: (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

Step A: Ethyl (*R)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate. A solution of A solution of ethyl (*R)-3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 172, 200 mg, 0.47 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 140 mg, 0.58 mmol), and triphenylphosphine (198 mg, 0.75 mmol) in THF (5 mL) was stirred at room temperature for 5 minutes. DBAD (174 mg, 0.76 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (300 mg, 98% yield). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=2.3 Hz, 1H), 8.23 (dd, J=2.4, 0.9 Hz, 1H), 8.07-8.01 (m, 2H), 7.53 (d, J=2.3 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 4.95 (t, J=7.8 Hz, 1H), 4.31 (s, 1H), 4.07 (dq, J=11.4, 7.2 Hz, 2H), 3.52 (d, J=15.3 Hz, 1H), 3.13 (dd, J=16.1, 7.4 Hz, 1H), 3.04 (dd, J=16.1, 8.3 Hz, 1H), 2.81 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 2.22 (t, J=3.9 Hz, 1H), 2.01 (s, 1H), 1.26-1.18 (m, 3H), 1.16 (t, J=7.1 Hz, 2H), 0.67-0.58 (m, 2H).

Step B: (*R)-3-(8-Methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid. Sodium hydroxide solution(1 M, 4.3 mL, 4.3 mmol) was added to a solution of ethyl (*R)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (300 mg, 0.47 mmol) in THF (5 mL). The reaction was stirred at room temperature overnight. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (280 mg, 98% yield). MS (ESI): mass calcd. for C₂₄H₂₇F₃N₆O₅S, 616.2; m/z found, 617.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=2.2 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.11-8.01 (m, 2H), 7.64 (d, J=2.2 Hz, 1H), 7.41 (s, 3H), 6.96 (d, J=7.3 Hz, 1H), 4.31 (s, 1H), 3.46 (d, J=0.8 Hz, 2H), 3.17 (dd, J=16.0, 7.8 Hz, 1H), 3.06 (dd, J=16.0, 7.7 Hz, 1H), 2.79 (s, 3H), 2.42 (d, J=19.7 Hz, 6H), 1.15 (s, 2H), 0.58 (s, 2H).

Example 566: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

Step A: (R/S)-Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate. A solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 49, 300 mg, 0.72 mmol), 2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 5, 231 mg, 1.02 mmol), and triphenylphosphine (280 mg, 1.07 mmol) in THF (8 mL) was stirred at room temperature for 5 minutes. Diisopropyl azodicarboxylate (0.23 mL, 1.18 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (400 mg, 89% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₂N₅O₅S, 625.2; m/z found, 626.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.42 (dd, J=4.8, 1.9 Hz, 1H), 8.25 (dd, J=7.6, 2.0 Hz, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.68-7.58 (m, 1H), 7.48-7.40 (m, 1H), 7.33-7.26 (m, 1H), 7.19 (s, 1H), 7.11-7.01 (m, 2H), 4.74 (s, 1H), 4.34-4.22 (m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.55-3.44 (m, 2H), 2.69 (s, 3H), 2.28 (s, 3H), 2.01 (s, 1H), 1.33 (d, J=34.9 Hz, 6H), 1.28-1.11 (m, 2H), 0.57-0.47 (m, 2H).

Step B: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid. Lithium iodide (342 mg, 2.56 mmol) was added to a solution of (R/S)-methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (400 mg, 0.64 mmol) in pyridine (14 mL). The reaction mixture was heated at 150° C. for 6 hours. Concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (342 mg, 83% yield). MS (ESI): mass calcd. for C₃₀H₃₁F₂N₅O₅S, 611.2; m/z found, 612.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.58 (s, 1H), 8.41 (dd, J=4.9, 1.9 Hz, 1H), 8.25 (dd, J=7.7, 1.9 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.38-7.22 (m, 2H), 7.22 (d, J=10.0 Hz, 1H), 7.15-7.05 (m, 2H), 4.78 (s, 1H), 4.29 (d, J=14.4 Hz, 1H), 4.24 (d, J=14.3 Hz, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.50-3.41 (m, 1H), 2.62 (s, 3H), 2.28 (s, 3H), 1.39 (s, 3H), 1.32 (s, 3H), 1.05 (s, 2H), 0.45 (s, 2H).

Example 567: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The mixture of (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid isomers (Example 566, 317 mg) was separated by chiral SFC (stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobile phase: 65% CO₂, 35% iPrOH) to afford two diastereomers. The first eluting isomer (129 mg, 33%) was designated (*S): MS: mass calcd. for C₃₀H₃₁F₂N₅O₅S, 611.2; m/z found, 612.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.46 (dd, J=4.9, 1.9 Hz, 1H), 8.30 (dd, J=7.6, 2.0 Hz, 1H), 8.17 (d, J=7.3 Hz, 1H), 7.33 (dd, J=7.7, 4.8 Hz, 1H), 7.26-7.22 (m, 1H), 7.16 (s, 1H), 7.12 (d, J=1.2 Hz, 2H), 4.81 (s, 1H), 4.36-4.27 (m, 2H), 3.55 (d, J=15.5 Hz, 1H), 3.46 (d, J=15.6 Hz, 1H), 2.70 (s, 3H), 2.31 (s, 3H), 1.42 (s, 3H), 1.37 (s, 3H), 1.22 (d, J=6.1 Hz, 1H), 1.12 (dt, J=10.0, 5.4 Hz, 1H), 1.05 (dt, J=12.2, 5.4 Hz, 1H), 1.03-0.94 (m, 1H), 0.55-0.48 (m, 2H).

Example 568: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting isomer (128 mg, 33%) from the chiral separation described in Example 567 was designated (*R): MS: mass calcd. for C₃₀H₃₁F₂N₅O₅S, 611.2; m/z found, 612.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.38 (dd, J=4.9, 2.0 Hz, 1H), 8.22 (dd, J=7.6, 2.0 Hz, 1H), 8.09 (d, J=7.3 Hz, 1H), 7.24 (dd, J=7.6, 4.9 Hz, 1H), 7.19-7.13 (m, 2H), 7.07 (d, J=3.1 Hz, 1H), 7.03 (d, J=1.3 Hz, 1H), 4.72 (s, 1H), 4.28-4.18 (m, 2H), 3.47 (d, J=15.3 Hz, 1H), 2.61 (s, 3H), 2.23 (s, 3H), 1.33-1.29 (m, 6H), 1.13 (d, J=6.1 Hz, 3H), 1.04 (dt, J=8.9, 4.9 Hz, 1H), 1.03-0.94 (m, 1H), 0.48-0.38 (m, 2H).

Example 569: (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (R/S)-Methyl 3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. Methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 169, 200 mg, 0.46 mmol), 2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 36, 153 mg, 0.57 mmol), and triphenylphosphine (192 mg, 0.73 mmol) in THF (8 mL) was stirred at room temperature for 5 minutes. DBAD (169 mg, 0.73 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (250 mg, 79% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.51 (m, 1H), 8.36 (dd, J=12.6, 2.2 Hz, 1H), 8.25-8.16 (m, 1H), 8.08 (d, J=7.3 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.36-7.18 (m, 2H), 4.79 (s, 1H), 4.64-4.48 (m, 1H), 4.45 (d, J=16.3 Hz, 1H), 4.18-4.00 (m, 2H), 3.77-3.64 (m, 3H), 3.65 (s, 3H), 3.49 (d, J=15.3 Hz, 1H), 2.80 (s, 3H), 2.45 (s, 3H), 1.84-1.51 (m, 4H), 1.41 (d, J=18.7 Hz, 6H).

Step B: (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. Lithium hydroxide (59 mg, 2.4 mmol) was added to a solution of (R/S)-methyl 3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (250 mg, 0.36 mmol) in MeOH (13 mL) and water (12 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (190 mg, 78% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.39 (m, 2H), 8.12-7.97 (m, 2H), 7.74 (d, J=2.2 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.24-7.16 (m, 1H), 4.90 (s, 1H), 4.45 (d, J=16.3 Hz, 1H), 4.36 (d, J=16.3 Hz, 1H), 4.06-3.90 (m, 2H), 3.63-3.54 (m, 2H), 3.40 (s, 3H), 2.76 (s, 3H), 2.37 (s, 3H), 1.65-1.51 (m, 2H), 1.58-1.40 (m, 2H), 1.38 (s, 3H), 1.31 (s, 3H).

Example 570: (*S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The mixture of (R/S)-3-(5-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers (184 mg) was separated by chiral SFC (stationary phase: Chiralpak IC 5 μm 250*21.2 mm, Mobile phase: 70% CO₂, 30% MeOH(0.3% iPrNH₂)) to afford two diastereomers. The first eluting isomer (77 mg, 29%) was designated (*S): MS: mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.52 (dd, J=4.9, 2.0 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.31-7.23 (m, 2H), 4.94 (s, 1H), 4.57 (d, J=15.8 Hz, 1H), 4.35 (d, J=15.8 Hz, 1H), 4.17-4.00 (m, 2H), 3.73-3.65 (m, 2H), 3.57 (s, 2H), 3.46 (s, 2H), 3.23-3.17 (m, 1H), 2.80 (s, 3H), 2.42 (s, 3H), 1.67 (s, 2H), 1.64-1.52 (m, 1H), 1.29-1.25 (m, 5H).

Example 571 (*R)-3-(5-((1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (90 mg, 34%) from the chiral separation described in Example 570 was designated (*R): MS: mass calcd. for C₃₁H₃₃F₃N₆O₆S, 674.2; m/z found, 675.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.52 (dd, J=4.9, 2.0 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.31-7.25 (m, 2H), 4.94 (s, 1H), 4.57 (d, J=15.9 Hz, 1H), 4.35 (d, J=15.9 Hz, 1H), 4.17-4.00 (m, 2H), 3.73-3.65 (m, 2H), 3.57 (s, 1H), 3.50 (s, 1H), 2.79 (s, 3H), 2.42 (s, 3H), 1.71-1.60 (m, 3H), 1.66-1.50 (m, 1H), 1.30 (s, 3H), 1.27-1.20 (m, 4H).

Example 572: (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

Step A: (R/S)-Methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate. Methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 169, 200 mg, 0.46 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 136 mg, 0.57 mmol), and triphenylphosphine (192 mg, 0.73 mmol) in THF (8 mL) was stirred at room temperature for 5 minutes. DBAD (169 mg, 0.73 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (200 mg, 66% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₅S, 658.2; m/z found, 659.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.31-8.22 (m, 1H), 8.23-8.16 (m, 1H), 8.03-7.91 (m, 2H), 7.54 (d, J=2.4 Hz, 1H), 7.10 (d, J=7.4 Hz, 1H), 4.68 (s, 1H), 4.34-4.24 (m, 1H), 4.21 (d, J=15.5 Hz, 1H), 3.57 (s, 2H), 3.57 (d, J=18.9 Hz, 1H), 3.50 (d, J=11.5 Hz, 1H), 2.88 (s, 1H), 2.82-2.77 (m, 1H), 2.70 (s, 2H), 2.42 (d, J=17.0 Hz, 3H), 2.34 (d, J=0.9 Hz, 3H), 1.38 (s, 1H), 1.30 (d, J=19.0 Hz, 5H), 1.26-1.10 (m, 2H), 0.63-0.56 (m, 2H).

Step B: (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid. Lithium hydroxide (49 mg, 2.0 mmol) was added to a solution of (R/S)-methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (200 mg, 0.30 mmol) in MeOH (20 mL) and water (10 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (150 mg, 77% yield). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=2.2 Hz, 1H), 8.27 (dd, J=2.5, 0.9 Hz, 1H), 8.13 (d, J=7.3 Hz, 1H), 8.06 (dd, J=2.5, 0.8 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 4.94 (s, 1H), 4.38 (d, J=15.7 Hz, 1H), 4.29 (d, J=15.6 Hz, 1H), 3.56 (s, 2H), 2.84 (s, 3H), 2.51 (s, 3H), 2.42 (s, 3H), 1.44-1.38 (m, 6H), 1.26 (d, J=12.6 Hz, 1H), 1.20 (s, 2H), 0.68-0.60 (m, 2H).

Example 573: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The mixture of (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid isomers (Example 572, 144 mg) was separated by chiral SFC (stationary phase: Chiralpak IC 5 μm 250*21.2 mm, Mobile phase: 60% CO₂, 40% MeOH) to afford two enantiomers. The first eluting isomer (41 mg, 21%) was designated (*S): MS: mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.49-8.45 (m, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 4.93 (s, 1H), 4.35 (d, J=15.7 Hz, 1H), 4.28 (d, J=15.7 Hz, 1H), 3.55 (s, 2H), 2.83 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H), 1.41 (s, 3H), 1.35 (s, 3H), 1.29-1.22 (m, 1H), 1.23-1.16 (m, 2H), 0.61 (q, J=3.2, 2.7 Hz, 2H).

Example 574: (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The second eluting isomer (40 mg, 20%) from the chiral separation described in Example 573 was designated (*R): MS: mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.47 (s, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.71 (s, 1H), 7.32 (d, J=7.4 Hz, 1H), 4.93 (s, 1H), 4.35 (d, J=15.6 Hz, 1H), 4.28 (d, J=15.7 Hz, 1H), 3.55 (s, 2H), 2.83 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H), 1.26 (d, J=6.8 Hz, 1H), 1.27-1.16 (m, 2H), 0.66-0.60 (m, 2H).

Example 575: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: (R/S)-Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 49, 500 mg, 1.20 mmol), 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 430 mg, 1.51 mmol), and triphenylphosphine (466 mg, 1.78 mmol) in THF (33 mL) and DMF (3 ml) was stirred at room temperature for 5 minutes. DBAD (454 mg, 2.0 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (800 mg, 98% yield). MS (ESI): mass calcd. for C₃₄H₃₉F₂N₅O₆S, 683.3; m/z found, 684.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) 8.28 (dd, J=2.4, 0.9 Hz, 1H), 8.17 (d, J=7.3 Hz, 1H), 8.03-7.97 (m, 1H), 7.72-7.63 (m, 2H), 7.59-7.51 (m, 1H), 7.50-7.42 (m, 2H), 7.27-7.19 (m, 1H), 7.18-7.07 (m, 1H), 4.81 (s, 1H), 4.51 (d, J=15.2 Hz, 1H), 4.44 (d, J=15.3 Hz, 1H), 4.03 (td, J=11.6, 2.2 Hz, 1H), 3.61 (s, 3H), 3.50 (s, 2H), 3.47-3.42 (m, 1H), 2.95 (s, 3H), 2.88 (s, 3H), 2.77 (s, 2H), 2.39 (s, 3H), 1.72-1.62 (m, 1H), 1.53-1.43 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H).

Step B: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Lithium hydroxide (170 mg, 4.06 mmol) was added to a solution of methyl (R/S)-methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (800 mg, 1.02 mmol) in MeOH (7 mL) and water (4 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (680 mg, 99% yield). MS (ESI): mass calcd. for C₃₃H₃₇F₂N₅O₆S, 669.2; m/z found, 670.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (t, J=1.5 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.30-7.19 (m, 2H), 7.17 (dd, J=7.9, 1.9 Hz, 1H), 7.13-7.06 (m, 2H), 4.86 (s, 1H), 4.54-4.41 (m, 2H), 4.01-3.86 (m, 2H), 3.66-3.51 (m, 2H), 3.46 (s, 2H), 2.73 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 2.04 (s, 2H), 1.64-1.50 (m, 2H), 1.44 (s, 3H), 1.36 (s, 3H).

Example 576: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dim ethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3M-yl)methyl)phenyl)propanoic acid isomers (Example 575, 675 mg) was separated by chiral SFC (stationary phase: Chiralpak IC, Sum, 150×30 mm, Mobile phase: 35% ethanol, 65% CO₂) to afford two diastereomers. The first eluting isomer (275 mg, 40%) was designated (*S): MS: mass calcd. for C₃₃H₃₇F₂N₅O₆S, 669.2; m/z found, 670.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.30-8.26 (m, 1H), 8.14 (d, J=7.4 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.25-7.22 (m, 1H), 7.22-7.07 (m, 4H), 4.87 (s, 1H), 4.53 (d, J=14.5 Hz, 1H), 4.44 (d, J=14.5 Hz, 1H), 4.04-3.93 (m, 2H), 3.72 (q, J=7.0 Hz, 2H), 3.69-3.64 (m, 1H), 3.64-3.58 (m, 1H), 3.48 (s, 2H), 2.76 (s, 3H), 2.39 (s, 3H), 2.24 (s, 3H), 1.63-1.50 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H).

Example 577: (*R)-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (260 mg, 38%) from the chiral separation described in Example 576 was designated (*R): MS: mass calcd. for C₃₃H₃₇F₂N₅O₆S, 669.2; m/z found, 670.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.28 (d, J=2.6 Hz, 1H), 8.14 (d, J=7.2 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.22-7.10 (m, 3H), 7.09 (d, J=7.9 Hz, 1H), 4.87 (s, 1H), 4.52 (d, J=14.4 Hz, 1H), 4.45 (d, J=14.5 Hz, 1H), 3.98 (dt, J=21.4, 11.7 Hz, 2H), 3.76-3.59 (m, 4H), 3.48 (s, 2H), 2.76 (s, 3H), 2.39 (s, 3H), 2.24 (s, 3H), 1.60 (d, J=13.9 Hz, 2H), 1.44 (s, 3H), 1.35 (s, 3H).

Example 578: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dim ethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Methyl (S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 49, 600 mg, 1.44 mmol), 7′-((2-morpholinoethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 146, 810 mg, 2.02 mmol), and triphenylphosphine (641 mg, 2.40 mmol) in THF (16 mL) and DMF (1 ml) was stirred at room temperature for 5 minutes. DBAD (553 mg, 2.40 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (1.1 g, 96% yield). MS (ESI): mass calcd. for C₃₉H₄₈F₂N₆O₈S, 798.3; m/z found, 799.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J=7.3 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.23-7.19 (m, 1H), 7.17-7.08 (m, 3H), 6.64 (d, J=8.4 Hz, 1H), 5.30 (s, 1H), 4.81 (s, 1H), 4.47 (t, J=5.7 Hz, 3H), 4.40 (d, J=15.0 Hz, 1H), 4.05-3.95 (m, 2H), 3.77-3.71 (m, 4H), 3.62 (td, J=13.0, 4.6 Hz, 2H), 3.61 (s, 3H), 3.45 (s, 1H), 3.40 (s, 1H), 2.82-2.74 (m, 5H), 2.60-2.54 (m, 4H), 2.25 (s, 3H), 1.74-1.63 (m, 2H), 1.49-1.38 (m, 1H), 1.43 (s, 3H), 1.36 (s, 3H).

Step B: 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Lithium hydroxide (289 mg, 6.88 mmol) was added to a solution of methyl (R/S)-methyl 3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-(2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (1100 mg, 1.38 mmol) in MeOH (9 mL) and water (6 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (600 mg, 56% yield). MS (ESI): mass calcd. for C₃₄H₄₆F₂N₆O₈S, 784.3; m/z found, 785.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.14 (d, J=7.2 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.24-7.19 (m, 1H), 7.18-7.06 (m, 3H), 6.64 (d, J=8.4 Hz, 1H), 4.84 (s, 1H), 4.75-4.69 (m, 2H), 4.51 (d, J=14.5 Hz, 1H), 4.37 (d, J=14.6 Hz, 1H), 3.97 (t, J=4.8 Hz, 4H), 3.95-3.86 (m, 2H), 3.70-3.59 (m, 2H), 3.46 (s, 10H), 3.40 (s, 2H), 2.74 (s, 3H), 2.24 (s, 3H), 1.62 (d, J=14.0 Hz, 2H), 1.42 (s, 3H), 1.33 (s, 3H).

Example 579: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 578, 675 mg) was separated by chiral SFC (stationary phase: IG (2×25 cm). Mobile phase: 30% ethanol, 70% CO₂) to afford two enantiomers. The first eluting isomer (277 mg, 26%) was designated (*S): MS: mass calcd. for C₃₄H₄₆F₂N₆O₈S, 784.3; m/z found, 785.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.15 (d, J=7.2 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 7.23-7.15 (m, 3H), 7.10 (t, J=8.0 Hz, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.86 (s, 1H), 4.51-4.40 (m, 4H), 4.00-3.90 (m, 2H), 3.68 (t, J=4.7 Hz, 5H), 3.61 (d, J=11.1 Hz, 1H), 3.44 (s, 2H), 2.82-2.75 (m, 5H), 2.59 (t, J=4.7 Hz, 4H), 2.24 (s, 3H), 2.00 (s, 3H), 1.63 (d, J=14.0 Hz, 1H), 1.51 (d, J=12.1 Hz, 1H), 1.44 (s, 3H), 1.34 (s, 3H).

Example 580: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (260 mg, 24%) from the chiral separation described in Example 579 was designated (*R): MS: mass calcd. for C₃₈H₄₆F₂N₆O₈S, 784.3; m/z found, 785.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.14 (d, J=7.3 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.25-7.13 (m, 3H), 7.13-7.06 (m, 1H), 6.60 (d, J=8.4 Hz, 1H), 4.86 (s, 1H), 4.45 (td, J=5.7, 3.3 Hz, 4H), 4.00-3.90 (m, 2H), 3.71-3.66 (m, 5H), 3.62 (d, J=10.7 Hz, 1H), 3.44 (s, 2H), 2.82-2.75 (m, 5H), 2.58 (t, J=4.7 Hz, 4H), 2.23 (s, 3H), 2.00 (s, 3H), 1.63 (d, J=14.0 Hz, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 3H), 1.32 (s, 3H).

Example 581: 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

Step A: Methyl (S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A solution of methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 49, 600 mg, 1.44 mmol), 7′-((2-morpholinoethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 146, 810 mg, 2.02 mmol), and triphenylphosphine (641 mg, 2.40 mmol) in THF (16 mL) and DMF (1 ml) was stirred at room temperature for 5 minutes. DBAD (553 mg, 2.40 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (1.1 g, 96% yield). MS (ESI): mass calcd. for C₃₉H₄₈F₂N₆O₈S, 798.3; m/z found, 799.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J=7.3 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.23-7.19 (m, 1H), 7.17-7.08 (m, 3H), 6.64 (d, J=8.4 Hz, 1H), 5.30 (s, 1H), 4.81 (s, 1H), 4.47 (t, J=5.7 Hz, 3H), 4.40 (d, J=15.0 Hz, 1H), 4.05-3.95 (m, 2H), 3.77-3.71 (m, 4H), 3.62 (td, J=13.0, 4.6 Hz, 2H), 3.61 (s, 3H), 3.45 (s, 1H), 3.40 (s, 1H), 2.82-2.74 (m, 5H), 2.60-2.54 (m, 4H), 2.25 (s, 3H), 1.74-1.63 (m, 2H), 1.49-1.38 (m, 1H), 1.43 (s, 3H), 1.36 (s, 3H).

Step B: (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-((2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Lithium hydroxide (289 mg, 6.88 mmol) was added to a solution of methyl (R/S)-methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((7′-(2-morpholinoethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (1100 mg, 1.38 mmol) in MeOH (9 mL) and water (6 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (420 mg, 44% yield). MS (ESI): mass calcd. for C₃₃H₃₇F₂N₅O₇S, 685.2.3; m/z found, 686.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 9.71 (s, 1H), 8.16 (d, J=7.2 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.28-7.19 (m, 2H), 7.15 (dd, J=8.0, 1.9 Hz, 1H), 7.09 (t, J=7.0 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 5.28 (s, 1H), 4.84 (s, 1H), 4.50 (d, J=14.5 Hz, 1H), 4.49-4.38 (m, 2H), 4.04-3.92 (m, 5H), 3.65-3.53 (m, 2H), 3.43 (s, 2H), 2.66 (s, 3H), 2.23 (s, 3H), 1.65-1.56 (m, 2H), 1.45 (s, 1H), 1.43 (s, 3H), 1.35 (s, 3H).

Example 582: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The mixture of: 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid isomers (420 mg) was separated by chiral SFC (stationary phase: IG (2×25 cm). Mobile phase: 30% ethanol, 70% CO₂) to afford two enantiomers. The first eluting isomer (199 mg, 21%) was designated (*S): MS: mass calcd. for C₃₃H₃₇F₂N₅O₇S, 685.2.3; m/z found, 686.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.15 (d, J=7.3 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.26-7.11 (m, 4H), 7.10 (d, J=7.9 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.88 (s, 1H), 4.50 (d, J=14.5 Hz, 1H), 4.45 (d, J=14.5 Hz, 1H), 4.12-4.00 (m, 2H), 3.97 (s, 3H), 3.73 (q, J=7.0 Hz, 2H), 3.69-3.64 (m, 2H), 2.77 (s, 3H), 2.25 (s, 3H), 1.65 (d, J=14.1 Hz, 1H), 1.60 (d, J=14.3 Hz, 1H), 1.52 (s, 1H), 1.46 (s, 3H), 1.43 (d, J=11.3 Hz, 1H), 1.36 (s, 3H).

Example 583: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((7′-methoxy-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting isomer (203 mg, 22%) from the chiral separation described in Example 582 was designated (*R): MS: mass calcd. for C₃₃H₃₇F₂N₅O₇S, 685.2.3; m/z found, 686.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.16 (d, J=7.2 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.24 (dd, J=7.8, 4.7 Hz, 2H), 7.16 (dd, J=7.9, 1.9 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.31 (s, 1H), 4.88 (s, 1H), 4.52-4.42 (m, 2H), 4.07-3.99 (m, 2H), 3.97 (s, 3H), 3.72 (dd, J=15.1, 8.4 Hz, 1H), 3.65 (d, J=10.8 Hz, 1H), 3.47 (s, 2H), 2.76 (s, 3H), 2.25 (s, 3H), 1.65 (d, J=12.7 Hz, 2H), 1.60 (d, J=14.2 Hz, 2H), 1.46 (s, 3H), 1.37 (s, 3H).

Example 584: (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

Step A: Methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate. A solution of methyl 3-(5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 169, 300 mg, 0.69 mmol), 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 241 mg, 0.85 mmol), and triphenylphosphine (287 mg, 1.1 mmol) in THF (8 mL) and DMF (1.5 ml) was stirred at room temperature for 5 minutes. DBAD (253 mg, 1.1 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated under a stream of nitrogen and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound 480 mg, 99% yield). MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₆S, 702.2; m/z found, 703.3 [M+H]⁺. 1 H NMR (500 MHz, CDCl₃) δ 8.33-8.25 (m, 2H), 8.05 (d, J=7.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 5.26 (s, 1H), 4.75 (s, 1H), 4.48 (d, J=16.2 Hz, 1H), 4.41 (d, J=16.3 Hz, 1H), 4.07-3.98 (m, 2H), 3.61 (s, 5H), 3.49-3.43 (m, 1H), 2.75 (s, 3H), 2.38 (d, J=19.2 Hz, 6H), 1.73 (d, J=2.8 Hz, 1H), 1.68-1.48 (m, 3H), 1.39 (s, 3H), 1.34 (s, 3H).

Step B: (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid. Lithium hydroxide (110 mg, 4.60 mmol) was added to a solution of methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (480 mg, 0.68 mmol) in MeOH (23 mL) and water (22 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (456 mg, 97% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.06 (d, J=7.1 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 5.31 (s, 1H), 4.88 (s, 1H), 4.50 (d, J=16.1 Hz, 1H), 4.37 (d, J=16.1 Hz, 1H), 4.00 (t, J=11.1 Hz, 5H), 3.65-3.58 (m, 2H), 3.46 (q, J=7.1 Hz, 2H), 3.40 (s, 1H), 2.74 (s, 3H), 2.46 (s, 3H), 2.37 (s, 3H), 1.34 (S, 3H), 1.33 (s, 3H).

Example 585: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The mixture of (R/S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid isomers (Example 584, 456 mg) was separated by chiral SFC (stationary phase: Chiralpak IC, 2×25 cm, Mobile phase: 35% methanol, 65% CO₂, 0.2% NPA) to afford two enantiomers. The first eluting isomer (210 mg) was designated (*S): MS: mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.4 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.46 (d, J=2.0 Hz, 1H), 8.32 (dd, J=2.5, 0.9 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.37 (d, J=7.4 Hz, 1H), 5.31 (s, 1H), 4.95 (s, 1H), 4.55 (d, J=15.9 Hz, 1H), 4.42 (d, J=16.0 Hz, 1H), 4.06 (td, J=11.6, 2.3 Hz, 2H), 3.92 (s, 5H), 3.69 (d, J=10.6 Hz, 2H), 3.54 (s, 2H), 2.86 (s, 3H), 2.46 (s, 3H), 2.42 (s, 3H), 1.44 (s, 3H), 1.36 (s, 3H).

Example 586: (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid

The second eluting isomer (215 mg) from the chiral separation described in Example 585 was designated (*R): MS: mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.4 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.47 (d, J=2.4 Hz, 1H), 8.32 (dd, J=2.4, 0.9 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.99-7.95 (m, 1H), 7.82-7.78 (m, 1H), 7.38 (d, J=7.4 Hz, 1H), 5.31 (s, 1H), 4.95 (s, 1H), 4.55 (d, J=16.0 Hz, 1H), 4.42 (d, J=16.0 Hz, 1H), 4.18 (s, 5H), 4.09-4.02 (m, 2H), 3.68 (d, J=11.6 Hz, 2H), 3.53 (s, 2H), 2.85 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H), 1.44 (s, 3H), 1.37 (s, 3H).

Example 587: (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl (RS)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 170-racemic, 400 mg, 0.92 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 330 mg, 1.38 mmol) and triphenylphosphine (361 mg, 1.38 mmol) in THF (20 mL) was stirred at room temperature for 5 minutes. DBAD (317 mg, 1.38 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (530 mg, 88% yield). MS (ESI): mass calcd. for C₃₁H₃₃F₃N₆O₅S, 658.2; m/z found, 659.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.17 (dd, J=2.4, 0.9 Hz, 1H), 7.96 (dd, J=2.4, 0.8 Hz, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 6.98 (s, 1H), 4.90 (s, 1H), 4.24 (d, J=15.7 Hz, 1H), 4.16 (d, J=15.7 Hz, 1H), 3.55 (s, 4H), 3.45 (d, J=15.2 Hz, 1H), 2.81 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.32 (s, 3H), 1.31-1.10 (m, 5H), 0.62-0.48 (m, 2H).

Step B: (R/S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. TFA (0.2 mL) was added to a solution of (R/S)-methyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (530 mg, 0.81 mmol) in CH₃CN (23 mL) and water (23 mL). The reaction was stirred at 50° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (489 mg, 94% yield). MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.34 (t, J=3.7 Hz, 2H), 4.77 (s, 1H), 4.43-4.19 (m, 2H), 3.75-3.48 (m, 2H), 2.91 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H), 1.39 (s, 3H), 1.31 (s, 3H), 1.18 (d, J=6.0 Hz, 2H), 0.68-0.55 (m, 2H).

Example 588: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The mixture of (R/S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid isomers (Example 587, 489 mg) was separated by chiral SFC (stationary phase: CHIRALPAK IG 250*20 mm, Mobile phase: 70% CO₂, 30% MeOH) to afford two diastereomers. The first eluting isomer (242 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₁F₃N₆O₅S, 644.2; m/z found, 645.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.29 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.25 (s, 1H), 4.78 (s, 1H), 4.28 (d, J=16.4 Hz, 1H), 4.18 (d, J=16.4 Hz, 1H), 3.60 (d, J=15.1 Hz, 1H), 3.47 (d, J=14.9 Hz, 1H), 2.86 (s, 3H), 2.33 (s, 3H), 2.17 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.19-1.14 (m, 2H), 0.59 (dd, J=6.8, 3.2 Hz, 2H).

Example 589: (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (241 mg) from the chiral separation described in Example 588 was designated (*R): MS: mass calcd. for C₃₂H₃₅F₃N₆O₆S, 674.2; m/z found, 675.3 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.35 (s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.93 (d, J=7.0 Hz, 1H), 7.62 (d, J=7.3 Hz, 1H), 7.29 (s, 1H), 4.73 (s, 1H), 4.35 (d, J=16.1 Hz, 1H), 4.26 (d, J=16.1 Hz, 1H), 3.68 (d, J=15.0 Hz, 1H), 3.54 (d, J=15.2 Hz, 1H), 2.90 (s, 3H), 2.42 (s, 3H), 2.24 (s, 3H), 1.32 (d, J=17.6 Hz, 6H), 1.08 (t, J=7.1 Hz, 2H), 0.66 (d, J=4.2 Hz, 2H).

Example 590: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-44(8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl (*S)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 170, 160 mg, 0.37 mmol), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 137, 182 mg, 0.51 mmol) and triphenylphosphine (142 mg, 0.54 mmol) in THF (10 mL) and DMF (3 mL) was stirred at room temperature for 5 minutes. DBAD (140 mg, 0.61 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to afford the title compound (218 mg, 77% yield). MS (ESI): mass calcd. for C₃₇H₄₄F₃N₇O₆S, 771.3; m/z found, 772.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.06 (s, 1H), 4.97 (s, 1H), 4.48 (t, J=5.9 Hz, 2H), 4.28 (d, J=15.6 Hz, 1H), 4.21 (d, J=15.7 Hz, 1H), 3.62 (s, 3H), 3.60-3.44 (m, 2H), 2.90 (d, J=8.3 Hz, 5H), 2.69-2.65 (m, 4H), 2.63-2.60 (m, 1H), 2.27-2.16 (m, 6H), 1.82 (p, J=3.2 Hz, 3H), 1.40 (s, 3H), 1.32 (s, 3H), 1.28-1.20 (m, 2H), 0.67-0.54 (m, 2H).

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. TFA (0.4 mL) was added to a solution of methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (218 mg, 0.81 mmol) in CH₃CN (8 mL) and water (8 mL). The reaction was stirred at 50° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (180 mg, 84% yield). MS (ESI): mass calcd. for C₃₆H₄₂F₃N₇O₆S, 757.3; m/z found, 758.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.36 (s, 1H), 7.26 (d, J=7.4 Hz, 1H), 4.75-4.69 (m, 3H), 4.31 (d, J=16.9 Hz, 1H), 4.25 (d, J=16.8 Hz, 1H), 3.97 (s, 2H), 3.64-3.53 (m, 4H), 2.99 (s, 2H), 2.94 (s, 3H), 2.28 (s, 3H), 2.17 (d, J=28.3 Hz, 8H), 1.43 (s, 3H), 1.33 (s, 3H), 1.28-1.17 (m, 1H), 1.21-1.13 (m, 1H), 0.63-0.51 (m, 2H).

Example 591: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl (*S)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 170, 250 mg, 0.57 mmol), 8′-methyl-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 37, 201 mg, 0.71 mmol) and triphenylphosphine (239 mg, 0.91 mmol) in THF (12 mL) and DMF (1 mL) was stirred at room temperature for 5 minutes. DBAD (211 mg, 0.92 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (380 mg, 94% yield). MS (ESI): mass calcd. for C₃₃H₃₇F₃N₆O₆S, 702.2; m/z found, 703.2 [M+H]⁺.

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-44(8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. TFA (0.8 mL) was added to a solution of methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (380 mg, 0.54 mmol) in CH₃CN (15 mL) and water (15 mL). The reaction was stirred at 50° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (280 mg, 75% yield). MS (ESI): mass calcd. for C₃₂H₃₅F₃N₆O₆S, 688.2; m/z found, 689.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 8.29 (dd, J=2.4, 0.9 Hz, 1H), 7.96-7.88 (m, 2H), 7.38-7.32 (m, 2H), 5.29 (s, 1H), 4.81 (s, 1H), 4.52 (d, J=17.1 Hz, 1H), 4.37 (d, J=17.0 Hz, 1H), 4.05-3.97 (m, 2H), 3.68-3.56 (m, 4H), 3.46 (q, J=7.0 Hz, 1H), 2.93 (s, 3H), 2.24 (s, 3H), 1.68 (d, J=15.2 Hz, 2H), 1.64-1.58 (m, 2H), 1.49-1.43 (m, 1H), 1.41 (s, 3H), 1.34 (s, 3H).

Example 592: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-44(8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-44(8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl (*S)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 170, 160 mg, 0.37 mmol), 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 136, 189 mg, 0.51 mmol) and triphenylphosphine (142 mg, 0.54 mmol) in THF (7 mL) and DMF (3 mL) was stirred at room temperature for 5 minutes. DBAD (140 mg, 0.61 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to afford the title compound (218 mg, 76% yield). MS (ESI): mass calcd. for C₃₄H₄₆F₃N₇O₆S, 785.3; m/z found, 786.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.35 (s, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.06 (s, 1H), 4.98 (s, 1H), 4.46 (t, J=6.0 Hz, 2H), 4.28 (d, J=15.6 Hz, 1H), 4.21 (d, J=15.6 Hz, 1H), 3.62 (s, 3H), 3.50 (d, J=17.3 Hz, 2H), 2.90 (s, 3H), 2.77 (t, J=6.0 Hz, 2H), 2.56-2.50 (m, 4H), 2.24 (s, 3H), 2.19 (d, J=0.8 Hz, 3H), 1.61 (t, J=5.7 Hz, 4H), 1.49-1.38 (m, 5H), 1.32 (s, 3H), 1.20 (p, J=6.1 Hz, 2H), 0.67-0.55 (m, 2H).

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. TFA (0.4 mL) was added to a solution of methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (218 mg, 0.28 mmol) in CH₃CN (8 mL) and water (8 mL). The reaction was stirred at 50° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (155 mg, 72% yield). MS (ESI): mass calcd. for C₃₇H₄₄F₃N₇O₆S, 771.3; m/z found, 772.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 8.29 (dd, J=2.4, 0.9 Hz, 1H), 7.96-7.88 (m, 2H), 7.38-7.32 (m, 2H), 5.29 (s, 1H), 4.81 (s, 1H), 4.52 (d, J=17.1 Hz, 1H), 4.37 (d, J=17.0 Hz, 1H), 4.05-3.97 (m, 2H), 3.68-3.56 (m, 4H), 3.46 (q, J=7.0 Hz, 1H), 2.93 (s, 3H), 2.24 (s, 3H), 1.68 (d, J=15.2 Hz, 2H), 1.60 (tq, J=13.7, 5.0, 4.1 Hz, 2H), 1.49-1.43 (m, 1H), 1.41 (s, 3H), 1.34 (s, 3H).

Example 593: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl (*S)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 170, 160 mg, 0.37 mmol), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 144, 204 mg, 0.51 mmol) and triphenylphosphine (142 mg, 0.54 mmol) in THF (7 mL) and DMF (3 mL) was stirred at room temperature for 5 minutes. DBAD (140 mg, 0.61 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to afford the title compound (280 mg, 94% yield). MS (ESI): mass calcd. for C₃₉H₄₈F₃N₇O₇S, 815.3; m/z found, 816.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.35 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.79 (d, J=1.0 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.09 (s, 1H), 5.03 (s, 1H), 4.51 (t, J=6.0 Hz, 2H), 4.41 (d, J=16.4 Hz, 1H), 4.35 (d, J=16.3 Hz, 1H), 4.12-3.99 (m, 2H), 3.64 (s, 5H), 3.49 (s, 3H), 2.92 (d, J=7.0 Hz, 5H), 2.71-2.64 (m, 4H), 2.24-2.18 (m, 6H), 1.88-1.78 (m, 4H), 1.76-1.68 (m, 1H), 1.59-1.46 (m, 2H), 1.43 (s, 3H), 1.34 (s, 3H).

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-44(8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. Lithium hydroxide (65 mg, 2.7 mmol) was added to a solution of methyl (*S)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (220 mg, 0.27 mmol) in THF (11 mL) and water (5 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound to provide the title compound (206 mg, 95% yield). MS (ESI): mass calcd. for C₃₄H₄₆F₃N₇O₇S, 801.3; m/z found, 802.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 13.42 (s, 1H), 8.39 (s, 1H), 7.94 (d, J=7.3 Hz, 1H), 7.80 (d, J=1.0 Hz, 1H), 7.36 (s, 1H), 7.29 (d, J=7.5 Hz, 1H), 4.76 (s, 2H), 4.76 (d, J=10.7 Hz, 1H), 4.46 (d, J=17.2 Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 4.03-3.89 (m, 4H), 3.76-3.67 (m, 1H), 3.65-3.56 (m, 1H), 3.59 (s, 5H), 2.97 (s, 3H), 2.27 (s, 3H), 2.24-2.12 (m, 7H), 1.82-1.66 (m, 3H), 1.66-1.50 (m, 2H), 1.40 (d, J=37.2 Hz, 6H).

Example 594: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: Methyl (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A solution of methyl (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (Intermediate 171, 150 mg, 0.38 mmol), 8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 6, 127 mg, 0.53 mmol), and triphenylphosphine (146 mg, 0.56 mmol) in THF (19 mL) was stirred at room temperature for 5 minutes. DBAD (144 mg, 0.63 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (220 mg, 94% yield). MS (ESI): mass calcd. for C₃₂H₃₈N₆O₅S, 618.3; m/z found, 619.3 [M+H]⁺.

Step B: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. Lithium hydroxide (85 mg, 3.6 mmol) was added to a solution of methyl (*S)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (220 mg, 0.36 mmol) in THF (16 mL) and water (6 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was approximately 6. DCM was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (180 mg, 84% yield). MS (ESI): mass calcd. for C₃₁H₃₆N₆O₅S, 604.3; m/z found, 605.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.99 (dd, J=2.4, 0.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.27-7.17 (m, 2H), 4.72 (s, 1H), 4.64-4.50 (m, 2H), 4.30 (d, J=16.4 Hz, 1H), 4.23 (d, J=16.4 Hz, 1H), 4.10 (q, J=7.1 Hz, 1H), 3.51 (s, 2H), 3.00 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H), 2.02 (s, 1H), 1.53 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.23 (d, J=7.1 Hz, 1H), 1.16 (s, 2H), 0.59-0.45 (m, 2H).

Example 595: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: 3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid. Tetrabutylammonium fluoride (1 M in THF, 5.1 ml, 5.1 mmol) was added to a solution of methyl 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (Intermediate 171, step B, 1.3 g, 2.5 mmol) in THF (28 ml) and 3 drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous NaHCO₃, then extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to an oil under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (400 mg, 41% yield). MS (ESI): mass calcd. for C₂₁H₂₆N₄O₃, 382.2; m/z found, 383.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ d 8.16 (s, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.98 (s, 1H), 5.06 (s, 1H), 4.57-4.43 (m, 4H), 3.48 (s, 3H), 2.80 (s, 3H), 2.08 (s, 3H), 1.47 (t, J=7.3 Hz, 3H), 1.32 (d, J=3.9 Hz, 3H), 1.13 (d, J=5.7 Hz, 3H).

Step B: Benzyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. (Bromomethyl)benzene (0.15 mL, 1.26 mmol) was added to a solution of 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid (400 mg, 1.05 mmol), potassium carbonate (361 mg, 2.62 mmol) in ACN (20 mL). The resultant mixture was stirred at room-temperature for 16 hours. Quenched with water (10 mL) and extracting with ethyl acetate (20 mL×3). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the compound, which was purified by FCC (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound. MS (ESI): mass calcd. for C₂₈H₃₂N₄O₃, 472.2; m/z found, 473.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.14 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28-7.20 (m, 3H), 7.19-7.12 (m, 3H), 7.03 (s, 1H), 5.16 (s, 1H), 5.07-4.97 (m, 2H), 4.56 (q, J=7.3 Hz, 4H), 3.12 (s, 1H), 2.84 (s, 3H), 2.14 (s, 3H), 1.56 (t, J=7.3 Hz, 3H), 1.47 (s, 3H), 1.26 (s, 3H).

Step C: The mixture of (R/S)-benzyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (470 mg) was purified and separated by chiral SFC (stationary phase: AD-H 2*25 cm, Mobile phase: 75% CO₂, 25% EtOH) to afford two enantiomers. The first eluting isomer (226 mg) was designated (*S): MS (ESI): mass calcd. for C₂₈H₃₂N₄O₃, 472.2; m/z found, 473.3 [M+H]⁺. The second eluting isomer was designated as (*R), however this Intermediate was not used further.

Step D: tert-Butyl (*S)-2′-((2-(3-(benzyloxy)-1-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-oxopropyl)-5-methylpyridin-4-yl)methyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. A solution of (*S)-benzyl 3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (200 mg, 0.42 mmol), tert-butyl 8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 153, 211 mg, 0.59 mmol), and triphenylphosphine (164 mg, 0.62 mmol) in THF (21 mL) was stirred at room temperature for 5 minutes. DBAD (161 mg, 0.70 mmol) was added and the solution was stirred at room temperature for 30 minutes. The reaction was then concentrated and purified by flash column chromatography (eluent: 0-100% ethyl acetate/hexanes) to afford the title compound (250 mg, 73% yield). MS (ESI): mass calcd. for C₄₃H₅₁N₇O₇S, 809.4; m/z found, 810.3 [M+H]⁺.

Step E: (*S)-3-(44(1-(tert-Butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid. A solution of tert-Butyl (*S)-2′-((2-(3-(benzyloxy)-1-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-oxopropyl)-5-methylpyridin-4-yl)methyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (250 mg, 0.31 mmol) in methanol (31 mL) was subjected to hydrogenation reduction conditions on a continuous flow hydrogenation apparatus, such as the H-cube system, at 50° C. (20% Pd(OH)₂/carbon cartridge, flow rate=1 mL/min). Material was circulated through system for roughly 40 min at which time all starting material had been consumed. Solvent was removed and the residue (200 mg, 90%) was carried to next step without further purification. MS (ESI): mass calcd. for C₃₆H₄₅N₇O₇S, 719.3; m/z found, 720.3 [M+H]⁺.

Step F: (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. TFA (7 mL) was added to a solution of (*S)-3-(4-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid (200 mg, 0.28 mmol) in DCM (14 mL). The reaction was stirred at room temperature for one hour. And then concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (eluent: 0-10% MeOH/DCM) to provide the title compound (120 mg, 70% yield). MS (ESI): mass calcd. for C₃₁H₃₇N₇O₅S, 619.3; m/z found, 620.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 10.16 (s, 1H), 8.40 (d, J=7.2 Hz, 1H), 8.31 (s, 1H), 8.00-7.96 (m, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.58 (q, J=7.4 Hz, 3H), 4.42 (d, J=16.8 Hz, 1H), 4.25 (d, J=11.7 Hz, 1H), 4.13 (dd, J=25.9, 13.8 Hz, 3H), 4.06 (s, 1H), 3.94 (d, J=15.4 Hz, 1H), 3.29 (s, 3H), 2.78 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.53 (d, J=14.8 Hz, 3H), 1.40-1.31 (m, 6H).

Example 596: (*S)-3-(3-((7′-((2-(3-fluoroazetidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (36 mg, 63%) was prepared using analogous conditions as described in Example 370 where 7′-((2-(3-fluoroazetidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 177) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134) in step A. MS (ESI): mass calcd. for C₃₆H₄₀F₄N₆O₆S, 760.3; m/z found, 761.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.94 (s, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.19 (dd, J=7.9, 2.0 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.09 (s, 1H), 5.23-5.19 (m, 0.5H), 5.11-5.07 (m, 0.5H), 4.77 (s, 1H), 4.28-4.23 (m, 2H), 4.16 (q, J=14.5 Hz, 2H), 3.69-3.57 (m, 2H), 3.53-3.13 (m, 4H), 2.82 (t, J=5.3 Hz, 2H), 2.62 (s, 3H), 2.24 (s, 3H), 2.17 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 0.98-0.89 (m, 2H), 0.59-0.44 (m, 2H).

Example 597: (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (250 mg, 55%) was prepared using analogous conditions as described in Example 370 where 8′-methyl-7′-((2-morpholinoethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 178) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134) in step A. MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₇S, 772.3; m/z found, 773.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.94 (d, J=1.0 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.19 (dd, J=7.9, 1.9 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.10-7.07 (m, 1H), 4.77 (s, 1H), 4.38 (t, J=5.8 Hz, 2H), 4.25-4.08 (m, 2H), 3.58-3.54 (m, 4H), 3.51-3.25 (m, 2H), 2.69 (t, J=5.8 Hz, 2H), 2.62 (s, 3H), 2.49-2.42 (m, 4H), 2.25 (s, 3H), 2.16 (s, 3H), 1.28 (s, 3H), 1.21 (s, 3H), 1.01-0.88 (m, 2H), 0.59-0.43 (m, 2H).

Example 598: (*S)-3-(3-((1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (45 mg, 51%) was prepared using analogous conditions as described in Example 370 where 7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 179) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134) in step A. MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₆S, 742.3; m/z found, 743.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (d, J=7.3 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.26 (d, J=7.4 Hz, 1H), 7.22-7.16 (m, 1H), 7.16-7.07 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 4.76 (s, 1H), 4.35 (t, J=5.7 Hz, 2H), 4.27-4.08 (m, 2H), 3.65-3.07 (m, 5H), 2.77 (t, J=5.8 Hz, 2H), 2.62 (s, 3H), 2.24 (s, 3H), 1.71-1.65 (m, 4H), 1.33-1.14 (m, 7H), 0.97-0.93 (s, 2H), 0.61-0.50 (m, 2H).

Example 599: (*S)-3-(3-((7′-(3-amino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Benzyl (*S)-3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a solution of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (860 mg, 1.68 mmol, Intermediate 71), tert-butyl 3-(1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5[oxathiazepin]-7′-yl)propanoate (953 mg, 2.36 mmol, Intermediate 180), PPh₃ (652 mg, 2.49 mmol) in a 1:1 mix of THF (13.5 mL)/DMF (13.5 mL) at room temperature was added DIAD (0.56 mL, 2.84 mmol). The mixture was stirred for 45 min. at room temperature and then poured into saturated bicarbonate and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate/hexanes, 0:1 to 70:30, gradient) to give the title compound (1225 mg, 82%). MS (ESI): mass calcd. for C₄₆H₅₂F₃N₅O₈S, 891.3; m/z found, 892.4 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.26 (d, J=7.4 Hz, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.21-7.16 (m, 2H), 7.13-7.03 (m, 6H), 5.09 (d, J=12.2 Hz, 1H), 4.92 (d, J=12.2 Hz, 1H), 4.75 (s, 1H), 4.41-4.32 (m, 2H), 3.81-3.69 (m, 2H), 3.35 (d, J=1.8 Hz, 4H), 3.00 (t, J=7.0 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.54 (s, 3H), 2.16 (s, 3H), 1.49-1.29 (m, 19H).

Step B: (*S)-3-(2′-(5-(3-benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid. Benzyl (*S)-3-(3-((7′-(3-(tert-butoxy)-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (500 mg, 0.56 mmol) was dissolved in a 1:1 mixture of DCM (2.5 mL) and TFA (2.5 mL) and allowed to stir at room temperature for 1 h. The solvent was then removed under reduced pressure and the resulting residue dissolved in a 1:1 mixture of MeCN/DCM, which was removed under reduced pressure to give the title compound (561 mg, 105%). This material was used in the next step without purification. ¹H NMR (600 MHz, DMSO-d₆) δ 8.17 (d, J=7.3 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.16-7.06 (m, 3H), 7.05-6.91 (m, 6H), 5.66 (s, 2H), 5.00 (d, J=12.2 Hz, 1H), 4.83 (d, J=12.2 Hz, 1H), 4.66 (s, 1H), 4.28 (s, 2H), 3.72-3.50 (m, 2H), 3.40-3.25 (m, 3H), 2.92 (t, J=7.1 Hz, 2H), 2.60 (t, J=7.1 Hz, 2H), 2.45 (s, 3H), 2.08 (s, 3H), 1.42-1.20 (m, 9H).

Step C: Benzyl (*S)-3-(3-((7′-(3-amino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. TEA (0.14 mL, 1.0 mmol) was added to a solution of (*S)-3-(2′-(5-(3-benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid (167 mg, 0.20 mmol), ammonium chloride (107 mg, 2.0 mmol), and HATU (228 mg, 0.60 mmol) in DCM (5.0 mL). After stirring at room temperature for 24 h the reaction mixture was poured into saturated, aqueous sodium chloride and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: MeOH/DCM, 0:1 to 15:85, gradient) to give the title compound (46 mg, 28%). MS (ESI): mass calcd. for C₄₂H₄₅F₃N₆O₇S, 834.3; m/z found, 835.2 [M+H]⁺.

Step D: (*S)-3-(3-((7′-(3-amino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (39 mg, 95%) was prepared using analogous conditions as described in Example 126, where benzyl (*S)-3-(3-((7′-(3-amino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of benzyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethyoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]propanoate in step B. MS (ESI): mass calcd. for C₃₅H₃₉F₃N₆O₇S, 744.3; m/z found, 745.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.42 (d, J=7.2 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.36 (s, 1H), 7.31-7.21 (m, 4H), 7.14 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 4.81 (s, 1H), 4.50-4.30 (m, 2H), 3.81-3.72 (m, 2H), 3.51-3.37 (m, 3H), 3.35-3.26 (m, 3H), 2.96 (t, J=7.5 Hz, 2H), 2.66 (s, 3H), 2.18 (s, 3H), 1.47-1.34 (m, 4H), 1.32 (s, 3H), 1.27 (s, 3H).

Example 600: (*S) 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: (*S) tert-butyl 2,2-dimethyl-3-(4-methyl-3-((8-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propane-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. The title compound (214 mg, 68%) was prepared using analogous conditions as described in Example 126) where 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 181) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 72) and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 71) in step A. MS (ESI): mass calcd. for C₄₅H₅₉F₃N₆O₇S, 884.4; m/z found, 885.3 [M+H]⁺.

Step B: (*S) 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (115 mg, 57%) was prepared using analogous conditions as described in Example 370) where tert-butyl 2,2-dimethyl-3-(4-methyl-3-((8-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propane-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate was used instead of tert-butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a][pyridine-7-yl)propanoate in Step B. MS (ESI): mass calcd. for C₄₁H₅₁F₃N₆O₇S, 828.3; m/z found, 829.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 7.31-7.19 (m, 3H), 7.15 (dd, J=8.0, 2.7 Hz, 1H), 5.32-5.26 (m, 1H), 4.81 (s, 1H), 4.50-4.27 (m, 2H), 3.82-3.69 (m, 2H), 3.51-3.25 (m, 3H), 2.66 (d, J=2.0 Hz, 3H), 2.60 (ddd, J=13.0, 6.3, 2.0 Hz, 1H), 2.47-2.36 (m, 5H), 2.19 (d, J=1.9 Hz, 3H), 2.12 (s, 3H), 1.57-1.21 (m, 20H).

Example 601: (*S) 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 600) were separated by chiral SFC (Stationary phase: Chiracel OJ-H 5 μm 250*30 mm, Mobile phase: 90% CO₂, 10% EtOH (w/0.3% i-PrNH₂)) to afford two diastereomers. The first eluting isomer (45 mg) was designated (*R): MS (ESI): mass calcd. for C₄₁H₅₁F₃N₆O₇S, 828.3; m/z found, 829.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=7.2 Hz, 1H), 7.84 (d, J=0.9 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.27 (dd, J=7.9, 1.9 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 4.80 (s, 1H), 4.42 (d, J=15.2 Hz, 1H), 4.30 (d, J=15.1 Hz, 1H), 3.74 (q, J=10.6 Hz, 2H), 3.52-3.08 (m, 4H), 2.65-2.54 (m, 4H), 2.45-2.37 (m, 5H), 2.19 (s, 3H), 2.12 (s, 3H), 1.56-1.40 (m, 6H), 1.39-1.13 (m, 14H).

Example 602: (*S) 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*S)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of (*S) 2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3 [1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid isomers (Example 600) were separated by chiral SFC (Stationary phase: Chiracel OJ-H 5 μm 250*30 mm, Mobile phase: 90% CO₂, 10% EtOH (w/0.3% i-PrNH₂)) to afford two diastereomers. The second eluting isomer (43 mg) was designated (*S): MS (ESI): mass calcd. for C₄₁H₅₁F₃N₆O₇S, 828.3; m/z found, 829.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=7.2 Hz, 1H), 7.84 (d, J=1.0 Hz, 1H), 7.34 (d, J=7.3 Hz, 1H), 7.26 (dd, J=7.9, 1.9 Hz, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 4.80 (s, 1H), 4.42-4.31 (m, 2H), 3.74 (dd, J=11.6, 8.9 Hz, 2H), 3.55-3.07 (m, 4H), 2.65-2.55 (m, 4H), 2.44-2.38 (m, 5H), 2.19 (s, 3H), 2.12 (s, 3H), 1.54-1.40 (m, 6H), 1.39-1.15 (m, 14H).

Example 603: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The mixture of (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((1-piperidin-1-yl)propan-2-yl)amino)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid (Example 376) isomers were separated by chiral SFC (Stationary phase: Chiralpak IG 5 μm 250*30 mm, Mobile phase: 55% CO₂, 45% MeOH (w/0.3% i-PrNH₂)) to afford two diastereomers. The second eluting isomer, designated as (*S), was not isolated. The first eluting isomer (40 mg) was designated (*R): ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=7.2 Hz, 1H), 7.48 (d, J=0.9 Hz, 1H), 7.34 (d, J=7.3 Hz, 1H), 7.25 (dd, J=7.8, 1.9 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 6.32 (d, J=7.3 Hz, 1H), 4.79 (s, 1H), 4.40-4.16 (m, 3H), 3.83-3.73 (m, 2H), 3.50-3.08 (m, 3H), 2.60 (s, 3H), 2.47-2.38 (m, 3H), 2.37-2.28 (m, 2H), 2.28-2.16 (m, 4H), 2.05 (s, 3H), 1.51-1.42 (m, 6H), 1.41-1.11 (m, 14H).

Example 604: (*S)-3-(3-((7′-((2-(Azetidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (44 mg, 59%) was prepared using analogous conditions as described in Example 370) where 7′-((2-azetidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 182) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134) in step A. MS (ESI): mass calcd. for C₃₆H₄₁F₃N₆O₆S, 742.3; m/z found, 743.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.2 Hz, 1H), 7.93 (d, J=0.9 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 7.22-7.16 (m, 1H), 7.15-7.04 (m, 2H), 4.76 (s, 1H), 4.26-4.09 (m, 4H), 3.50-3.14 (m, 6H), 2.75-2.65 (m, 2H), 2.61 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H), 1.97 (p, J=6.9 Hz, 2H), 1.33-1.11 (m, 6H), 0.93 (s, 2H), 0.59-0.42 (m, 2H).

Example 605: (*S)-3-(3-((7′-(3-Cyclobutylamino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Benzyl (*S)-3-(3-((7′-(3-cyclobutylamino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. To a solution of (*S)-3-(2′-(5-(3-benzyloxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-oxopropyl)-2-methylbenzyl)-1′,1′-dioxido-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-7′-yl)propanoic acid (400 mg, 0.45 mmol, Example 599, Step B), and HATU (364 mg, 0.98 mmol) in DMF (8.0 mL) was added cyclobutyl amine (102 mg, 1.4 mmol) followed by TEA (0.21 mL, 1.5 mmol). After stirring at room temperature for 18 h. the reaction was poured into water and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate/hexanes, 0:1 to 1:0, gradient) to give the title compound (204 mg, 48%). MS (ESI): mass calcd. for C₄₆H₅₁F₃N₆O₇S, 888.3; m/z found, 889.2 [M+H]⁺.

Step B: (*S)-3-(3-((7′-(3-cyclobutylamino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. The title compound (90 mg, 49%) was prepared using analogous conditions as described in Example 126 where benzyl (*S)-3-(3-((7′-(3-cyclobutylamino-3-oxopropyl)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridine-7-yl)propanoate was used instead of benzyl (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethyoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]propanoate in Step B. MS (ESI): mass calcd. for C₃₉H₅₁F₃N₆O₇S, 798.3; m/z found, 799.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.33-7.20 (m, 4H), 7.14 (d, J=7.9 Hz, 1H), 4.81 (s, 1H), 4.45 (d, J=15.5 Hz, 1H), 4.34 (d, J=15.5 Hz, 1H), 4.23-4.10 (m, 1H), 3.74 (q, J=10.3 Hz, 2H), 3.52-3.24 (m, 4H), 2.99-2.93 (m, 2H), 2.65 (s, 3H), 2.51-2.44 (m, 2H), 2.21-2.08 (m, 5H), 1.91-1.77 (m, 2H), 1.66-1.54 (m, 2H), 1.46-1.28 (m, 7H), 1.25 (s, 3H).

Example 606: (*S)-3-(3-((7′-((2-Hydroxyethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: Methyl (*S)-3-(3-((7′-((2-hydroxyethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate. DIAD (0.08 mL, 0.41 mmol) was added to a solution of methyl (*S)-3-(3-hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (100 mg, 0.23 mmol, Intermediate 145), 7′-((2-hydroxyethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (106 mg, 0.31 mmol Intermediate 183) and PPh₃ (89 mg, 0.34 mmol) in a mixture of THF (3.0 mL) and DMF (1.0 mL) at room temperature After stirring for 45 minutes the reaction was poured into saturated bicarbonate and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: ethyl acetate/hexanes, 0:1 to 1:0, gradient) to give the title compound (114 mg, 66%). MS (ESI): mass calcd. for C₃₅H₄₀F₃N₅O₈S, 747.2; m/z found, 748.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=7.2 Hz, 1H), 8.01 (dd, J=8.5, 1.4 Hz, 1H), 7.24-7.17 (m, 3H), 7.14 (d, J=7.7 Hz, 1H), 6.78 (dd, J=8.3, 1.3 Hz, 1H), 5.76 (d, J=1.3 Hz, 1H), 4.89 (t, J=5.6 Hz, 1H), 4.80 (s, 1H), 4.50-4.26 (m, 4H), 3.55 (s, 3H), 3.53-3.34 (m, 4H), 3.32 (d, J=1.3 Hz, 5H), 2.68 (s, 3H), 2.18 (s, 3H), 1.59-1.37 (m, 4H), 1.36 (s, 3H), 1.30 (s, 3H).

Step B: (*S)-3-(3-((7′-((2-hydroxyethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. methyl (*S)-3-(3-((7′-((2-hydroxyethoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (106 mg, 0.14 mmol) was dissolved in MeOH (1.2 mL), THF (1.2 mL) and 2M aqueous LiOH (0.5 mL) and heated to 60° C. for 18 h. The reaction was cooled, pH adjusted to 5.0 with 1N HCl and extracted with ethyl acetate (4×). These extractions resulted in several fractions that were combined, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by reverse phase HPLC (eluent: MeCN/H₂O w/20 mM NH₄OH, 0:1 to 70:30, gradient) to give the title compound (30 mg, 29%). MS (ESI): mass calcd. for C₃₄H₃₈F₃N₅O₈S, 733.2; m/z found, 734.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (d, J=7.2 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.13 (d, J=2.0 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 4.80 (s, 1H), 4.73 (s, 1H), 4.37 (d, J=15.4 Hz, 1H), 4.29-4.20 (m, 3H), 3.65 (q, J=7.4, 5.7 Hz, 4H), 3.37 (t, J=13.8 Hz, 3H), 2.58 (s, 3H), 2.11 (s, 3H), 1.41 (s, 2H), 1.24 (s, 5H), 1.18 (s, 4H).

Example 607: (*S)-3-(3-((7′-(3-(3-Hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (*S)-Methyl 3-(3-((7′-(3-(3-hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution consisting of (*S)-methyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 160, 250 mg) and CH₃CN (5 mL) was added dropwise to a 0° C. (ice/water) mixture consisting of 7′-(3-(3-hydroxypropoxy)propoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 187, 200 mg, 0.55 mmol), K₂CO₃ (200 mg, 1.45 mmol), and CH₃CN (5 mL). The resultant mixture was stirred at 90° C. for 2 hours, then was poured into water (20 mL) and extracted with ethyl acetate (30 mL×3). These organic solvent fractions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to afford the product, which was purified by FCC (eluent: petroleum ether/ethyl acetate=50:1 to 5:1) to afford the title compound (200 mg, 47.6%) as a gray solid. MS (ESI): mass calcd. for C₃₉H₄₈F₃N₅O₉S, 819.31; m/z found, 820.2 [M+H]⁺.

Step B: (*S)-3-(3-((7′-(3-(3-Hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. LiOH.H₂O (100 mg, 2.38 mmol) was added into to a mixture consisting of (*S)-methyl 3-(3-((7′-(3-(3-hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (200 mg, 0.244 mmol), MeOH (2 mL), THF (2 mL), and H₂O (2 mL). The resultant mixture was stirred at 65° C. for 12 hours, then was concentrated to dryness under reduced pressure and adjusted to pH=3-4 with 1 N HCl (2 mL). The mixture was concentrated to dryness under reduced pressure, then purified by preparative acidic HPLC (Xtimate C18, 150 mm×25 mm×5 μm column (eluent: 50% to 64% (v/v) CH₃CN and H₂O with 0.225% HCOOH)) to give the title compound (81.1 mg, 67.6%) as a white solid. MS (ESI): mass calcd. for C₃₄H₄₆F₃N₅O₉S, 805.30; m/z found, 806.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.53 (br. s, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.29-7.24 (m, 2H), 7.22 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.81 (s, 1H), 4.48-4.41 (m, 1H), 4.37-4.28 (m, 3H), 3.88-3.65 (m, 2H), 3.56-3.39 (m, 9H), 2.66 (s, 3H), 2.19 (s, 3H), 2.03-1.88 (m, 2H), 1.72-1.57 (m, 2H), 1.56-1.46 (m, 2H), 1.45-1.33 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H).

Example 608: (*R)-3-(3-((7′-(3-(3-Hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: (*R)-Methyl3-(3-((7′-(3-(3-hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 7′-(3-(3-Hydroxypropoxy)propoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 187, 185 mg, 0.460 mmol), (*R)-methyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 161210 mg, 0.463 mmol), K₂CO₃ (250 mg, 1.81 mmol), and CH₃CN (6 mL) were combined. The resultant mixture was stirred at 50° C. for 5 hours, then was concentrated to dryness under reduced pressure and purified by FCC (eluent: petroleum ether/ethyl acetate=1:0 to 3:1) to afford the title compound (265 mg, 70%) as a yellow solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₉H₄₈F₃N₅O₉S, 819.31; m/z found, 820.3 [M+H]⁺.

Step B: (*R)-3-(3-((7′-(3-(3-Hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. (*R)-Methyl 3-(3-((7′-(3-(3-hydroxypropoxy)propoxy)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (265 mg, 0.323 mmol) was added to a solution consisting of LiOH.H₂O (80 mg, 2.0 mmol), THF (3 mL), MeOH (3 mL), and H₂O (3 mL). The resultant mixture was stirred at 70° C. for 10 hours, then adjusted to pH to 6-7 with 1 N HCl, diluted with H₂O (2 mL), and extracted with ethyl acetate (5 ml×2). These organic solvent fractions were combined, concentrated to dryness under reduced pressure, and purified by preparative acidic HPLC (Xtimate C18, 150 mm×25 mm×5 μm column (eluent: 50% to 64% (v/v) CH₃CN and H₂O with 0.225% HCOOH)) to give the title compound (120.2 mg, 46%) as a white solid. MS (ESI): mass calcd. for C₃₄H₄₆F₃N₅O₉S, 805.30; m/z found, 806.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (br. s, 1H), 8.42 (d, J=7.2 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.31-7.23 (m, 2H), 7.22 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.81 (s, 1H), 4.48-4.40 (m, 1H), 4.37-4.29 (m, 3H), 3.82-3.67 (m, 2H), 3.53-3.38 (m, 9H), 2.66 (s, 3H), 2.19 (s, 3H), 2.00-1.89 (m, 2H), 1.70-1.60 (m, 2H), 1.57-1.46 (m, 2H), 1.45-1.33 (m, 2H), 1.32 (s, 3H), 1.26 (s, 3H).

Example 609: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b)][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: tert-Butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of tert-butyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 135, 200 mg, 0.419 mmol), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 134, 233 mg, 0.59 mmol), and triphenylphosphine (165 mg, 0.628 mmol) in THF (4 mL) was stirred at room temperature for 2 minutes. DBAD (164 mg, 0.712 mmol) was added and the solution was stirred at room temperature for 30 min. The reaction was quenched with water and transferred to a separatory funnel. The aqueous was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, washed with brine dried over MgSO₄, filtered, concentrated, and purified by flash column chromatography (0-15% MeOH/DCM) to provide the title compound (300 mg, 84% yield). MS (ESI): mass calcd. for C₄₃H₅₅F₃N₆O₇S, 856.4; m/z found, 429.3 [M+2H]²⁺.

Step B: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The title compound (200 mg, 34%) was prepared using analogous conditions as described in Example 658 where tert-Butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate was used instead of tert-Butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate in step B. The mixture was treated with acetonitrile and water and lyophilized to provide the title compound as the TFA salt (320 mg, 99%). MS (ESI): mass calcd. for C₃₉H₄₇F₃N₆O₇S, 800.3; m/z found, 401.3 [M+H]²⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 7.92 (d, J=1.0 Hz, 1H), 7.30-7.22 (m, 2H), 7.20-7.09 (m, 2H), 4.82 (s, 1H), 4.62-4.59 (m, 2H), 4.51-4.29 (m, 2H), 3.79-3.58 (m, 6H), 3.53-3.11 (m, 6H), 2.66 (s, 3H), 2.22 (s, 3H), 2.19 (s, 3H), 2.10-2.01 (m, 2H), 1.92-1.88 (m, 2H), 1.50 (d, J=13.8 Hz, 2H), 1.43-1.24 (m, 8H).

Example 610: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid

Step A: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate. The title compound (670 mg) was prepared using analogous reaction conditions as described in Example 642, Step A where methyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (Intermediate 196) was used instead of tert-butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate and where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₆S, 642.2 m/z found, 643.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (dd, J=1.9, 4.9 Hz, 1H), 8.30 (d, J=7.3 Hz, 1H), 8.26 (dd, J=1.9, 7.7 Hz, 1H), 7.69 (t, J=51.6 Hz, 1H), 7.54 (dd, J=4.8, 7.8 Hz, 2H), 7.42 (d, J=7.3 Hz, 1H), 7.20 (d, J=7.8 Hz, 1H), 4.96 (s, 1H), 4.66 (d, J=7.8 Hz, 1H), 4.62-4.58 (m, 1H), 4.52 (d, J=7.8 Hz, 2H), 4.48-4.42 (m, 1H), 4.37-4.31 (m, 1H), 4.03 (s, 2H), 3.49 (s, 3H), 2.75 (s, 3H), 2.27 (s, 3H), 1.36 (s, 3H), 1.28 (s, 3H).

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid. A mixture of NaOH (585 mg, 14.6 mmol) and methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoate (940 mg, 1.46 mmol) in dioxane-water (1:1, 10 mL) was stirred at 60° C. After 5 hours, the mixture was allowed to cool to room temperature and then the pH was adjusted to 2-3 by adding 3 N aqueous HCl solution. The mixture was poured into water and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Xtimate C18, 150×40 mm×10 μm column, eluent: 30% to 80% (v/v) CH₃CN in H₂O with 0.2% HCOOH). The pure fractions were lyophilized to dryness to provide the title compound as a mixture of enantiomers as a white solid (460 mg, 50%). This mixture was further purified by SFC using a chiral stationary phase (Daicel Chiralcel OJ-H column, 250 mm×30 mm×5 eluent: 20% methanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers. The first eluting isomer (160.1 mg) was designated (*S): MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₆S, 628.2 m/z found, 629.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.65-8.62 (m, 1H), 8.30-8.24 (m, 2H), 7.68 (t, J=52.0 Hz, 1H), 7.56-7.51 (m, 3H), 7.26 (d, J=7.8 Hz, 1H), 4.96 (s, 1H), 4.67-4.61 (m, 2H), 4.52 (d, J=7.8 Hz, 2H), 4.39 (s, 2H), 4.10-3.96 (m, 2H), 2.75 (s, 3H), 2.27 (s, 3H), 1.34 (s, 3H), 1.28 (s, 3H).

Example 611: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(6-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid

The second eluting isomer (180.5 mg) for the chiral separation described in Example 610 was designated (*R): MS (ESI): mass calcd. for C₂₉H₃₀F₂N₆O₆S, 628.2 m/z found, 629.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.65-8.62 (m, 1H), 8.30-8.24 (m, 2H), 7.68 (t, J=51.6 Hz, 1H), 7.56-7.51 (m, 3H), 7.27 (d, J=7.8 Hz, 1H), 4.97 (s, 1H), 4.64 (t, J=8.7 Hz, 2H), 4.52 (d, J=7.8 Hz, 2H), 4.42-4.36 (m, 2H), 4.09-3.97 (m, 2H), 2.75 (s, 3H), 2.27 (s, 3H), 1.34 (s, 3H), 1.27 (s, 3H).

Example 612: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid

The title compound (89 mg, 15%) was prepared using analogous conditions as described in Example 624 where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 15 dioxide (Intermediate 59) was used instead of 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide, in step A. MS (ESI): mass calcd. for C₃₁H₃₄N₆O₆S 618.2 m/z found 619.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (dd, J=1.8, 4.8 Hz, 1H), 8.37-8.35 (m, 1H), 8.20 (dd, J=2.0, 7.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.68-7.65 (m, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.52 (dd, J=4.9, 7.7 Hz, 1H), 4.81 (s, 1H), 4.49-4.40 (m, 4H), 4.38-4.27 (m, 2H), 3.98-3.93 (m, 1H), 3.93-3.83 (m, 2H), 2.70 (s, 3H), 2.37 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.24-1.18 (m, 4H).

Example 613: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid

The title compound (127 mg, 22%) was prepared using analogous conditions as described in Example 624 where (*R)-methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (Intermediate 189) was used instead of (*S)-methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate and 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-15 dioxide (Intermediate 59) was used instead of 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide, in step A. MS (ESI): mass calcd. for C₃₁H₃₄N₆O₆S 618.2 m/z found 619.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (dd, J=1.9, 4.9 Hz, 1H), 8.37-8.35 (m, 1H), 8.20 (dd, J=1.9, 7.7 Hz, 1H), 7.72-7.69 (m, 1H), 7.68-7.66 (m, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.52 (dd, J=4.9, 7.7 Hz, 1H), 4.81 (s, 1H), 4.49-4.40 (m, 4H), 4.38-4.27 (m, 2H), 3.99-3.93 (m, 1H), 3.93-3.83 (m, 2H), 2.70 (s, 3H), 2.37 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.24-1.18 (m, 4H).

Example 614: (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (276 mg, 60%) was prepared using analogous conditions as described in Example 370 where 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 190) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) was used instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in step A. MS (ESI): mass calcd. for C₃₁H₃₂F₃N₅O₆S, 659.2; m/z found, 660.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.42 (m, 1H), 8.38 (d, J=7.2 Hz, 1H), 8.04-8.02 (m, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.27-7.20 (m, 2H), 7.16 (d, J=7.8 Hz, 1H), 4.80 (s, 1H), 4.45-4.32 (m, 3H), 4.32-4.24 (m, 2H), 4.20 (d, J=14.9 Hz, 1H), 3.74 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H), 1.30 (s, 3H), 1.24 (s, 3H).

Example 615: (*S)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (270 mg, 62%) was prepared using analogous conditions as described in Example 370 where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide and tert-butyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 128) was used instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in step A. MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅O₆S, 645.2; m/z found, 646.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (dd, J=4.9, 1.9 Hz, 1H), 8.38 (d, J=7.3 Hz, 1H), 8.21 (dd, J=7.7, 1.9 Hz, 1H), 7.51 (dd, J=7.7, 4.9 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.16 (d, J=7.7 Hz, 1H), 4.80 (s, 1H), 4.44-4.18 (m, 6H), 3.76 (s, 2H), 2.64 (s, 3H), 2.21 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H).

Example 616: (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3434(1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The title compound (234 mg, 54%) was prepared using analogous conditions as described in Example 370 where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide and tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 129) was used instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in step A. MS (ESI): mass calcd. for C₃₀H₃₁F₂N₅O₆S, 627.2; m/z found, 628.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (dd, J=4.9, 1.9 Hz, 1H), 8.37 (d, J=7.3 Hz, 1H), 8.21 (dd, J=7.7, 1.9 Hz, 1H), 7.70 (t, J=51.6 Hz, 1H), 7.51 (dd, J=7.7, 4.9 Hz, 1H), 7.29-7.20 (m, 3H), 7.15 (d, J=7.9 Hz, 1H), 4.77 (s, 1H), 4.47-4.18 (m, 6H), 3.80 (s, 2H), 2.61 (s, 3H), 2.21 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H).

Example 617: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The title compound (220 mg, 46%) was prepared using analogous conditions as described in Example 370 where 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 190) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide and tert-butyl (*S)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 129) was used instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in step A. MS (ESI): mass calcd. for C₃₁H₃₃F₂N₅O₆S, 641.2; m/z found, 642.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.42 (m, 1H), 8.36 (d, J=7.3 Hz, 1H), 8.05-8.02 (m, 1H), 7.70 (t, J=51.6 Hz, 1H), 7.29-7.20 (m, 3H), 7.15 (d, J=7.9 Hz, 1H), 4.77 (s, 1H), 4.46-4.17 (m, 6H), 3.77 (s, 2H), 2.61 (s, 3H), 2.38 (s, 3H), 2.21 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H).

Example 618: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Methyl 3-(3-((7′-chloro-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate. Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (Intermediate 186, 600 mg, 1.4 mmol) was dissolved in ACN (7 mL). 7′-Chloro-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 131, 467 mg, 1.7 mmol) and potassium carbonate (317 mg, 2.29 mmol) were added and the reaction was stirred at 80° C. overnight. After this time, the reaction was allowed to cool to room temperature, then was diluted with water and EtOAc and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-100% ethyl acetate/hexanes) to provide the title compound (593.7 mg, 63% yield). MS (ESI): mass calcd. for C₃₄H₃₈ClN₅O₅S, 663.2; m/z found, 664.3 [M+H]⁺.

Step B: Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. Methyl 3-(3-((7′-chloro-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (594 mg, 0.894 mmol), (S)-1-(piperidin-1-yl)propan-2-amine (574.6 mg, 4.04 mmol), and DMSO (4.5 mL) were combined and heated in a microwave reactor at 130° C. for 1 hour. After this time, the reaction was allowed to cool to room temperature, then was diluted with water and EtOAc and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure. The material was purified by flash column chromatography (0-10% MeOH/DCM) to provide the title compound (610 mg, 89% yield). MS (ESI): mass calcd. for C₄₂H₅₅N₇O₅S, 769.4; m/z found, 770.4 [M+H]⁺.

Step C: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′4(S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (610 mg, 0.79 mmol), LiOH (196 mg, 8.2 mmol), 1,4-dioxane (4 mL), and water (4 mL) were combined and heated to 75° C. for 3 hours. After this time, the reaction was allowed to cool to room temperature, and was acidified to pH 4 using 1M HCl. The biphasic mixture was separated and the aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound without further purification (410 mg, 68% yield). MS (ESI): mass calcd. for C₄₁H₅₃N₇O₅S, 755.4; m/z found, 756.4 [M+H]⁺.

Example 619: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Methyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. A solution of methyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 186, 209.7 mg, 0.515 mmol), 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 190, 146.1 mg, 0.57 mmol), and triphenylphosphine (229.6 mg, 0.875 mmol) in THF (2.6 mL) was stirred at room temperature for 1 minute. DBAD (194 mg, 0.843 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction was concentrated and purified by flash column chromatography (0-10% MeOH/DCM) to provide the title compound containing residual solvents (380 mg, 114% yield). MS (ESI): mass calcd. for C₃₄H₃₉N₅O₆S, 645.3; m/z found, 646.3 [M+H]⁺.

Step B: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Methyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (332.3 mg, 0.515 mmol) was dissolved in THF (2 mL). Tetrabutylammonium hydroxide 30-hydrate (2.097 g, 2.62 mmol) and water (2 mL) were added and the resulting mixture was stirred at 70° C. for 3.5 hours. After this time, the reaction was allowed to cool to room temperature, and was acidified to pH 3-4 using 1M HCl. The biphasic mixture was separated and the aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, washed with brine 3 times, dried over MgSO₄, filtered, concentrated, and purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH) to provide the title compound (173.4 mg, 53% yield). MS (ESI): mass calcd. for C₃₃H₃₇N₅O₆S, 631.2; m/z found, 632.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.26-8.22 (m, 1H), 7.96-7.91 (m, 1H), 7.82-7.76 (m, 1H), 7.24-7.20 (m, 1H), 7.06-6.99 (m, 2H), 6.92 (d, J=7.3 Hz, 1H), 4.84-4.79 (m, 1H), 4.74 (s, 1H), 4.67-4.46 (m, 3H), 4.13 (d, J=13.8 Hz, 1H), 3.99-3.90 (m, 1H), 3.85-3.70 (m, 2H), 2.64 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H), 1.97-1.86 (m, 1H), 1.31 (d, J=34.8 Hz, 6H), 1.13-0.97 (m, 4H).

Example 620: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The title compound (97.3 mg, 35.5%) was prepared using analogous conditions as described in Example 619 where 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₂H₃₅N₅O₆S, 617.2; m/z found, 618.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.57-8.52 (m, 1H), 8.28-8.23 (m, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.39-7.31 (m, 2H), 7.15-7.08 (m, 2H), 6.99 (d, J=7.3 Hz, 1H), 4.94 (d, J=7.2 Hz, 1H), 4.85 (s, 1H), 4.78-4.68 (m, 2H), 4.62 (d, J=7.2 Hz, 1H), 4.23 (d, J=13.8 Hz, 1H), 4.13-4.06 (m, 1H), 3.98-3.90 (m, 1H), 3.80-3.73 (m, 1H), 2.76 (s, 3H), 2.20 (s, 3H), 2.05-1.95 (m, 1H), 1.41 (d, J=35.3 Hz, 6H), 1.24-1.10 (m, 4H).

Example 621: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-((1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The title compound (95.8 mg, 30.7%) was prepared using analogous conditions as described in Example 619 where methyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 184) was used instead of methyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate, and 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 59) was used instead of 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₂H₃₅N₅O₆S, 617.2; m/z found, 618.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.59-8.51 (m, 1H), 8.29-8.21 (m, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.39-7.31 (m, 2H), 7.17-7.08 (m, 2H), 7.00 (d, J=7.3 Hz, 1H), 4.92 (d, J=7.3 Hz, 1H), 4.85 (s, 1H), 4.79-4.68 (m, 2H), 4.61 (d, J=7.3 Hz, 1H), 4.23 (d, J=13.8 Hz, 1H), 4.13-4.04 (m, 1H), 3.97-3.88 (m, 1H), 3.83-3.75 (m, 1H), 2.75 (s, 3H), 2.21 (s, 3H), 2.06-1.94 (m, 1H), 1.41 (d, J=34.6 Hz, 6H), 1.24-1.07 (m, 4H).

Example 622: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The title compound (97.3 mg, 35.5%) was prepared using analogous conditions as described in Example 619 where methyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 184) was used instead of methyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. MS (ESI): mass calcd. for C₃₃H₃₇N₅O₆S, 631.2; m/z found, 632.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.26-8.21 (m, 1H), 7.95-7.92 (m, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.23-7.20 (m, 1H), 7.06-6.99 (m, 2H), 6.91 (d, J=7.3 Hz, 1H), 4.83 (d, J=7.2 Hz, 1H), 4.74 (s, 1H), 4.67-4.59 (m, 2H), 4.51 (d, J=7.2 Hz, 1H), 4.12 (d, J=13.7 Hz, 1H), 4.00-3.91 (m, 1H), 3.86-3.77 (m, 1H), 3.75-3.66 (m, 1H), 2.66 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H), 1.95-1.85 (m, 1H), 1.31 (d, J=35.4 Hz, 6H), 1.15-0.98 (m, 4H).

Example 623: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic acid

The title compound (277 mg, 42%) was prepared using analogous conditions as described in Example 624 where (*R)-Methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (Intermediate 189) was used instead (*S)-Methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate in step A. MS (ESI): mass calcd. for C₃₂H₃₆N₆O₆S 632.2 m/z found 633.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47-8.44 (m, 1H), 8.38-8.34 (m, 1H), 8.05-8.00 (m, 1H), 7.72-7.65 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 4.81 (s, 1H), 4.46-4.40 (m, 4H), 4.36-4.25 (m, 2H), 3.98-3.93 (m, 1H), 3.93-3.81 (m, 2H), 2.70 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.24-1.18 (m, 4H).

Example 624: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic acid

Step A: (*S)-Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-54(8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate. (*S)-Methyl 3-((5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (475 mg, 1.11 mmol, Intermediate 188), 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (260 mg, 1.02 mmol, Intermediate 190), K₂CO₃ (770 mg, 5.57 mmol), and CH₃CN (10 mL) were added to a 40 mL round-bottomed flask. The resultant mixture was stirred at 80° C. for 8 hours before cooling to room-temperature, pouring into water (20 mL), and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to dryness under reduced pressure to give the title compound (670 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₃H₃₈N₆O₆S 646.3 m/z found 647.2 [M+H]⁺.

Step B: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic acid. LiOH.H₂O (425 mg, 10.1 mmol) was added to a solution of (*S)-methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-54(8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (650 mg, 1.01 mmol) and 1,4-dioxane: H₂O (1:1, 10 mL). The resulting mixture was stirred at 60° C. for 4 hours before adjusting the pH to 3 with 1 N HCl and extracting with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative reverse phase HPLC (eluent: MeCN/H₂O with 0.225% HCOOH 16% to 46%, gradient) to give the title compound (343 mg, 53%). MS (ESI): mass calcd. for C₃₂H₃₆N₆O₆S 632.2 m/z found 633.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47-8.43 (m, 1H), 8.37-8.34 (m, 1H), 8.04-8.02 (m, 1H), 7.72-7.65 (m, 2H), 7.59 (d, J=8.6 Hz, 1H), 4.81 (s, 1H), 4.46-4.39 (m, 4H), 4.37-4.25 (m, 2H), 3.98-3.93 (m, 1H), 3.93-3.81 (m, 2H), 2.70 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H), 1.24-1.19 (m, 4H).

Example 625: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5] ]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic acid

The title compound (150 mg, 23%) was prepared using analogous conditions as described in Example 628 where (*R)-Methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (Intermediate 189) was used instead of (*S)-Methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate in step A. MS (ESI): mass calcd. for C₃₄H₄₇N₇O₆S 729.3; m/z found 730.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34-8.30 (m, 1H), 7.93 (s, 1H), 7.68-7.64 (m, 1H), 7.61-7.57 (m, 1H), 7.57-7.55 (m, 1H), 4.78 (s, 1H), 4.38 (t, J=5.6 Hz, 2H), 4.24-4.14 (m, 2H), 3.99-3.92 (m, 1H), 2.81 (t, J=5.8 Hz, 2H), 2.68 (s, 3H), 2.57-2.52 (m, 6H), 2.39 (s, 3H), 2.17 (s, 3H), 1.71-1.66 (m, 4H), 1.26 (s, 3H), 1.26-1.22 (m, 4H), 1.21 (s, 3H), 1.02-0.95 (m, 2H), 0.66-0.55 (m, 2H).

Example 626: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (240.8 mg) for the chiral separation described in Example 627 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₆S, 642.2 m/z found, 643.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (br s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.28 (d, J=7.3 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.68 (t, J=51.6 Hz, 1H), 7.57-7.50 (m, 2H), 7.27 (d, J=7.7 Hz, 1H), 4.96 (s, 1H), 4.67-4.59 (m, 2H), 4.52 (d, J=7.7 Hz, 2H), 4.37 (s, 2H), 4.09-3.94 (m, 2H), 2.75 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.34 (s, 3H), 1.28 (s, 3H).

Example 627: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The title compound (50.5 mg) was prepared using analogous reaction conditions as described in Example 610 where 8′-methyl-2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 190) was used instead of 2′,3′-dihydrospiro[oxetane-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and the following chiral SFC separation conditions where used in Step B: Daicel Chiralpak IG column, 250 mm×30 mm×10 μm, eluent: 40% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers. The first eluting isomer (163.9 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₂F₂N₆O₆S, 642.2 m/z found, 643.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (br s, 1H), 8.46 (d, J=1.5 Hz, 1H), 8.28 (d, J=7.3 Hz, 1H), 8.08 (d, J=1.8 Hz, 1H), 7.74 (t, J=51.6 Hz, 1H), 7.57-7.50 (m, 2H), 7.27 (d, J=7.9 Hz, 1H), 4.96 (s, 1H), 4.63 (t, J=8.8 Hz, 2H), 4.52 (d, J=7.7 Hz, 2H), 4.37 (s, 2H), 4.09-3.94 (m, 2H), 2.75 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.34 (s, 3H), 1.28 (s, 3H).

Example 628: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidine-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]]oxathiazepin]-2′(3′H)-yl)methyl)pyridine-3-yl)propanoic acid

Step A: (*S)-Methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate. (*S)-Methyl 3-(5-(chloromethyl)-6-methylpyridin-3-yl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (480 mg, 1.12 mmol, Intermediate 188), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (360 mg, 1.02 mmol, Intermediate 137), K₂CO₃ (780 mg, 5.64 mmol), and CH₃CN (15 mL) were added to a 40 mL flask. The resulting suspension was stirred at 80° C. for 6 hours, cooled to room-temperature, poured it into water (30 mL), and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (1×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the product (700 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₉H₄₉N₇O₆S 743.4 m/z found 744.3 [M+H]⁺.

Step B: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid. n-Bu₄NOH (1.7 g, 16 mmol) was added to a solution of (*S)-methyl 3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoate (400 mg, 0.538 mmol) and t-BuOH:H₂O (3:1, 20 mL). The resulting mixture was stirred at 90° C. for 3 hours, poured into aqueous NH₄Cl (40 mL), and extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, washed with brine (3×), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative reverse phase HPLC (eluent: MeCN/H₂O with 0.225% HCOOH 12% to 42%, gradient) and the isolated product combined with another batch of (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid to afford the title compound (200 mg). MS (ESI): mass calcd. for C₃₄H₄₇N₇O₆S 729.3; m/z found 730.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34-8.29 (m, 1H), 7.93 (s, 1H), 7.69-7.62 (m, 1H), 7.60-7.53 (m, 2H), 4.78 (s, 1H), 4.42-4.35 (m, 2H), 4.23-4.16 (m, 2H), 4.00-3.92 (m, 1H), 2.81 (t, J=5.8 Hz, 2H), 2.68 (s, 3H), 2.59-2.52 (m, 6H), 2.39 (s, 3H), 2.17 (s, 3H), 1.74-1.63 (m, 4H), 1.25 (s, 3H), 1.25-1.21 (m, 4H), 1.20 (s, 3H), 1.04-0.93 (m, 2H), 0.67-0.53 (m, 2H).

Example 629: (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-64(8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The title compound was prepared (24 mg) was prepared using analogous reaction conditions as described in Example 630, Step B where the second eluting isomer from Example 630, Step A was used instead of the first eluting isomer from Example 630, Step A. MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₅S, 659.2 m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50-8.45 (m, 1H), 8.29 (d, J=7.1 Hz, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.79 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 4.82 (d, J=13.0 Hz, 1H), 4.69 (s, 1H), 4.26 (d, J=10.8 Hz, 1H), 4.03-3.98 (m, 1H), 3.94-3.89 (m, J=10.0 Hz, 2H), 3.86-3.74 (m, 4H), 2.68 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H).

Example 630: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-64(8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 2′-((6-(3-(tert-butoxy)-2,2-dimethyl-1-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxopropyl)-3-methylpyridin-2-yl)methyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. DIAD (162 mg, 0.801 mmol) was added dropwise to a stirring solution of tert-butyl 3-(6-(hydroxymethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 197 250 mg, 0.522 mmol), tert-butyl 8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 153, 223 mg, 0.627 mmol) and PPh₃ (222 mg, 0.846 mmol) in dichloromethane (10 mL) at 0° C. The mixture was allowed to slowly warm to room temperature over the course of 3 hours whereupon the mixture was poured into water and then extracted with dichloromethane. These extractions resulted in several organic solvent fractions which were combined, washed with brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Gemini-NX column, 150×30 mm×5 μm, eluent: 66% to 96% (v/v) CH₃CN in H₂O with 0.2% HCOOH) to afford the title compound as a mixture of enantiomers. This mixture was purified by SFC using a chiral stationary phase (Regis (S,S) Whelk-O1 column, 250 mm×30 mm, 10 μm, eluent: 50% isopropanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers. The first eluting isomer (120 mg) was designated (*S): MS (ESI): mass calcd. for C₃₉H₄₈F₃N₇O₇S, 815.3 m/z found, 816.3 [M+H]⁺. The second eluting isomer (110 mg) was designated (*R): MS (ESI): mass calcd. for C₃₉H₄₈F₃N₇O₇S, 815.3 m/z found, 816.3 [M+H]⁺.

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. A mixture containing the first eluting isomer from Example DK 518, Step A (160 mg, 0.196 mmol) and 4 M HCl solution in dioxane (10 mL) in dioxane-acetonitrile (3:1, 8 mL) was stirred at room temperature. After 24 hours, the mixture was concentrated to dryness under reduced pressure. The residue was purified by SFC using a chiral stationary phase (Daicel Chiralpak IG column, 250 mm×50 mm×10 μm, eluent: 50% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford the title compound (43 mg, 33%) as a white solid after concentrating to dryness by lyophilization. MS (ESI): mass calcd. for C₃₀H₃₂F₃N₇O₅S, 659.2 m/z found, 660.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50-8.45 (m, 1H), 8.29 (d, J=7.2 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.79 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 4.82 (d, J=13.0 Hz, 1H), 4.69 (s, 1H), 4.24 (d, J=10.8 Hz, 1H), 4.00 (d, J=15.6 Hz, 1H), 3.91 (d, J=10.0 Hz, 2H), 3.85-3.75 (m, 4H), 2.68 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H).

Example 631: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (30.4 mg) for the chiral separation described in Example 631 was designated (*R): MS (ESI): mass calcd. for C₃₀H₃₃F₂N₇O₅S, 641.2 m/z found, 642.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.7 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.67 (t, J=52 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.83 (d, J=13.2 Hz, 1H), 4.69 (s, 1H), 4.25 (d, J=10.8 Hz, 1H), 4.03-3.88 (m, 4H), 3.84-3.78 (m, 2H), 2.66 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 1.21-1.13 (m, 6H).

Example 632: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 2′4(6-(1-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-methoxy-2,2-dimethyl-3-oxopropyl)-3-methylpyridin-2-yl)methyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. The title compound (490 mg) was prepared using analogous reaction conditions as described in Example 642, Step A where methyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (Intermediate 196) was used instead of tert-butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate and tert-butyl 8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 153) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₆H₄₃F₂N₇O₇S, 755.3 m/z found, 756.3 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.40 (d, J=1.8 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.45 (br d, J=7.3 Hz, 1H), 7.35-7.19 (m, 1H), 7.11 (d, J=7.7 Hz, 1H), 5.10 (s, 1H), 4.57-4.49 (m, 2H), 4.06-3.93 (m, 6H), 3.55 (s, 3H), 2.82 (s, 3H), 2.46 (s, 3H), 2.36 (s, 3H), 1.48 (s, 3H), 1.42 (s, 9H).

Step B: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-64(8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. The title compound (400 mg) was prepared using analogous reaction conditions as described in Example 642, Step B where tert-butyl 2′-((6-(1-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-methoxy-2,2-dimethyl-3-oxopropyl)-3-methylpyridin-2-yl)methyl)-8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide was used instead of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. MS (ESI): mass calcd. for C₃₁H₃₅F₂N₇O₅S, 655.3 m/z found, 656.3 [M+H]⁺.

Step C: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. A mixture containing NaOH (68 mg, 1.7 mmol) and methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (340 mg, 0.519 mmol) in THF-water (1:1, 4 mL) was stirred at 75° C. After 6 hours, the mixture was allowed to cool to room temperature and then the pH was adjusted to 6-7 by adding 1 N aqueous HCl solution. The mixture was poured into water and then extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed with brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Boston Green ODS column, 150×30×5 μm column, eluent: 15% to 45% (v/v) CH₃CN in H₂O with 0.225% HCOOH) to give the title compound (190 mg, 54%) as a mixture of enantiomers. This mixture was purified by SFC using a chiral stationary phase (Daicel Chiralpak IG column, 250 mm×50 mm×10 eluent: 50% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers both of which were further purified by preparative HPLC (Xtimate C18 column, 150 mm×40 mm×10 μm (eluent: 15% to 45% (v/v) CH₃CN in water with 0.225% HCOOH). The first eluting isomer (35 mg) was designated (*S): MS (ESI): mass calcd. for C₃₀H₃₃F₂N₇O₅S, 641.2 m/z found, 642.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (d, J=1.7 Hz, 1H), 8.27 (d, J=7.3 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 7.67 (t, J=52 Hz, 1H), 7.67 (s, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 4.82 (d, J=13.0 Hz, 1H), 4.69 (s, 1H), 4.24 (d, J=10.5 Hz, 1H), 4.03-3.88 (m, 4H), 3.82-3.77 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H), 1.18 (s, 6H).

Example 633: (*R)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-64(8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (87.2 mg) for the chiral separation described in Example 634 was designated (*R): MS (ESI): mass calcd. for C₃₆H₄₂F₃N₇O₆S, 757.3 m/z found, 758.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=7.1 Hz, 1H), 7.99 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 4.95 (s, 1H), 4.42-4.37 (m, 2H), 4.35-4.23 (m, 2H), 3.73-3.61 (m, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.74 (s, 3H), 2.56-2.52 (m, 4H), 2.33 (s, 3H), 2.18 (s, 3H), 1.72-1.63 (m, 4H), 1.29 (s, 3H), 1.20 (s, 3H), 1.07-0.95 (m, 2H), 0.82 (s, 2H).

Example 634: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-64(8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-c]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. The title compound (500 mg) was prepared using analogous reaction conditions as described in Example 642, Step A using tert-butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 198) instead of tert-butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate and using 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 137) instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₄₀H₅₀F₃N₇O₆S, 813.2 m/z found, 814.4 [M+H]⁺.

Step B: (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. A mixture containing tert-butyl 2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (500 mg, 0.467 mmol) and 4 M HCl solution in dioxane (20 mL) in dioxane-acetonitrile (1:1, 10 mL) was stirred at room temperature. After 16 hours, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Xtimate C18 column, 150 mm×40 mm×10 μm (eluent: 25% to 55% (v/v) CH₃CN in water with 0.225% HCOOH) to afford a mixture of enantiomers. This mixture was further purified by SFC using a chiral stationary phase (Daicel Chiralpak IG column, 250 mm×50 mm×10 eluent: 50% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers. The first eluting isomer (88 mg) was designated (*S): MS (ESI): mass calcd. for C₃₆H₄₂F₃N₇O₆S, 757.3 m/z found, 758.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, J=7.3 Hz, 1H), 7.99 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 4.95 (s, 1H), 4.42-4.37 (m, 2H), 4.36-4.25 (m, 2H), 3.74-3.60 (m, 2H), 2.80 (t, J=5.7 Hz, 2H), 2.74 (s, 3H), 2.56-2.53 (m, 4H), 2.33 (s, 3H), 2.18 (s, 3H), 1.72-1.65 (m, 4H), 1.29 (s, 3H), 1.21 (s, 3H), 1.07-0.96 (m, 2H), 0.87-0.77 (m, 2H).

Example 635: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (57.6 mg) for the chiral separation described in Example 636 was designated (*R): MS (ESI): mass calcd. for C₃₆H₄₃F₂N₇O₆S, 739.3 m/z found, 740.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.30 (m, 2H), 7.90 (s, 1H), 7.84-7.56 (m, 1H), 7.34 (d, J=6.8 Hz, 1H), 7.16 (s, 1H), 4.95 (s, 1H), 4.36 (t, J=5.6 Hz, 2H), 4.22-4.13 (m, 2H), 3.66-3.59 (m, 2H), 3.52-3.46 (m, 4H), 2.78 (t, J=5.6 Hz, 2H), 2.72 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.69-1.64 (m, 4H), 1.25 (s, 3H), 1.22 (s, 3H), 1.00-0.91 (m, 2H), 0.75-0.60 (m, 2H).

Example 636: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The title compound (58.6 mg) was prepared using analogous reaction conditions as described in Example 640 where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 137) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A and following separation by SFC using a chiral stationary phase (Daicel Chiralpak IG column, 250 mm×50 mm, 10 μm, eluent: 50% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂). The first eluting isomer (58.6 mg) was designated (*S): MS (ESI): mass calcd. for C₃₆H₄₃F₂N₇O₆S, 739.3 m/z found, 740.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.31 (m, 2H), 7.89 (s, 1H), 7.84-7.56 (m, 1H), 7.30 (d, J=7.1 Hz, 1H), 7.14 (s, 1H), 4.94 (s, 1H), 4.37 (t, J=5.6 Hz, 2H), 4.23-4.12 (m, 2H), 3.86-3.67 (m, 2H), 3.44-3.42 (m, 4H), 2.79 (t, J=5.6 Hz, 2H), 2.73 (s, 3H), 2.20 (s, 3H), 2.14 (s, 3H), 1.70-1.66 (m, 4H), 1.28 (s, 3H), 1.25 (s, 3H), 0.99-0.90 (m, 2H), 0.73-0.56 (m, 2H).

Example 637: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (51 mg) for the chiral separation described in Example 638 was designated (*R): MS (ESI): mass calcd. for C₃₇H₄₅F₂N₇O₆S, 753.3 m/z found, 754.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36-8.31 (m, 2H), 7.89 (s, 1H), 7.84-7.57 (m, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.14 (s, 1H), 4.94 (s, 1H), 4.35 (t, J=5.9 Hz, 2H), 4.22-4.12 (m, 2H), 3.67-3.56 (m, 2H), 2.73 (s, 3H), 2.66-2.63 (m, 2H), 2.46-2.40 (m, 4H), 2.20 (s, 3H), 2.13 (s, 3H), 1.49-1.44 (m, 4H), 1.40-1.34 (m, 2H), 1.29 (s, 3H), 1.24 (s, 3H), 1.01-0.87 (m, 2H), 0.76-0.55 (m, 2H).

Example 638: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The title compound (50.5 mg) was prepared using analogous reaction and chiral SFC separation conditions as described in Example 640 where 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 136) was used instead of 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide in Step A. Example 638 was the first eluting isomer and designated (*S): MS (ESI): mass calcd. for C₃₇H₄₅F₂N₇O₆S, 753.3 m/z found, 754.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36-8.31 (m, 2H), 7.89 (s, 1H), 7.84-7.56 (m, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.14 (s, 1H), 4.95 (s, 1H), 4.35 (t, J=5.9 Hz, 2H), 4.22-4.13 (m, 2H), 3.70-3.57 (m, 2H), 2.73 (s, 3H), 2.66-2.63 (m, 2H), 2.44-2.39 (m, 4H), 2.20 (s, 3H), 2.13 (s, 3H), 1.51-1.43 (m, 4H), 1.39-1.33 (m, 2H), 1.28 (s, 3H), 1.24 (s, 3H), 1.02-0.87 (m, 2H), 0.77-0.53 (m, 2H).

Example 639: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (43.9 mg) for the chiral separation described in Example 640 was designated (*R): MS (ESI): mass calcd. for C₃₄H₄₇F₂N₇O₇S, 783.3 m/z found, 784.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.32 (m, 2H), 7.81 (s, 1H), 7.80-7.54 (m, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.17 (s, 1H), 4.97 (s, 1H), 4.44-4.36 (m, 4H), 3.85-3.74 (m, 2H), 3.69-3.53 (m, 4H), 3.50-3.40 (m, 4H), 2.81 (t, J=5.9 Hz, 2H), 2.74 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.70-1.65 (m, 4H), 1.61-1.49 (m, 4H), 1.32 (s, 3H), 1.27 (s, 3H).

Example 640: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. The title compound (340 mg) was prepared using analogous conditions as described in Example 642, Step A where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 134) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide. MS (ESI): mass calcd. for C₄₂H₅₅F₂N₇O₇S, 839.4 m/z found, 840.5 [M+H]⁺.

Step B: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. A 4 N HCl solution in dioxane (15 mL) was added to a stirring solution of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (340 mg, 0.405 mmol) in dioxane (10 mL). After 20 hours, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in dioxane (10 mL) and then a 4 N HCl solution in dioxane (15 mL) was added. After 60 hours, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Boston Green ODS column, 150 mm×30 mm×5 eluent: 15% to 45% (v/v) CH₃CN in H₂O with 0.225% HCOOH). The pure fractions were lyophilized to dryness to afford the title compound as a mixture of enantiomers (140 mg). This mixture was separated by SFC using a chiral stationary phase (Daicel Chiralpak AD-H column, 250 mm×30 mm, 5 eluent: 35% isopropanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers. The first eluting isomer (42.2 mg) was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₇F₂N₇O₇S, 783.3 m/z found, 784.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.32 (m, 2H), 7.81 (s, 1H), 7.80-7.54 (m, 1H), 7.29 (d, J=7.1 Hz, 1H), 7.18 (s, 1H), 4.97 (s, 1H), 4.45-4.34 (m, 4H), 3.85-3.73 (m, 2H), 3.68-3.49 (m, 4H), 3.48-3.39 (m, 4H), 2.80 (t, J=5.9 Hz, 2H), 2.74 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.68 (s, 4H), 1.62-1.48 (m, 4H), 1.31 (s, 3H), 1.27 (s, 3H).

Example 641: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (41.7 mg) for the chiral separation described in Example 642 was designated (*R): MS (ESI): mass calcd. for C₃₉H₄₉F₂N₇O₇S, 797.3 m/z found, 798.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=7.1 Hz, 1H), 8.33 (s, 1H), 7.81 (s, 1H), 7.80-7.55 (m, 1H), 7.28 (d, J=7.1 Hz, 1H), 7.17 (s, 1H), 4.97 (s, 1H), 4.43-4.35 (m, 4H), 3.85-3.73 (m, 2H), 3.67-3.60 (m, 2H), 2.73 (s, 3H), 2.72-2.64 (m, 4H), 2.45-2.42 (m, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 1.55-1.45 (m, 8H), 1.39-1.34 (m, 2H), 1.31 (s, 3H), 1.27 (s, 3H).

Example 642: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

Step A: tert-Butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A mixture containing tert-butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (Intermediate 192, 200 mg, 0.418 mmol), 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 72, 155 mg, 0.377 mmol), and potassium carbonate (290 mg, 2.10 mmol) in acetonitrile (8 mL) was stirred at 80° C. After 16 hours, the mixture was allowed to cool to room temperature, then poured into water, and then extracted with ethyl acetate. These extractions resulted in several organic solvent fractions which were combined, washed with brine solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (350 mg, 76%) which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₃H₅₇F₂N₇O₇S, 853.4 m/z found, 854.5 [M+H]⁺.

Step B: Methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-44(8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate. A mixture of tert-butyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (350 mg, 0.41 mmol), 4 N HCl in dioxane (8 mL) and 5 drops of methanol was stirred at room temperature. After 16 hours, additional 4 N HCl in dioxane (5 mL) was added. After 16 hours, the mixture was concentrated to dryness under reduced pressure to give the title compound (300 mg) which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₀H₅₁F₂N₇O₇S, 811.4 m/z found, 812.4 [M+H]⁺.

Step C: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid. A mixture containing methyl 3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoate (330 mg, 0.406 mmol) and LiOH.H₂O (170 mg, 4.25 mmol) in dioxane:water (1:1, 8 mL) was stirred at 60° C. After 8 hours, the mixture was allowed to cool to room temperature and the pH was adjusted to 6 by adding aqueous 1 M HCl solution. The mixture was concentrated to dryness under reduced pressure and the residue was purified by preparative HPLC (Xtimate C18, 150×40 mm×10 μm column, eluent: 20% to 50% (v/v) CH₃CN in H₂O with 0.2% HCOOH). The pure fractions were lyophilized to dryness to provide the title compound as a mixture of enantiomers as a yellow solid (140 mg). MS (ESI): mass calcd. for C₃₉H₄₉F₂N₇O₇S, 797.3 m/z found, 798.3 [M+H]⁺. This mixture was separated by SFC using a chiral stationary phase (Daicel Chiralpak AD-H column, 250 mm×30 mm, 5 μm, eluent: 35% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂) to afford two isomers. The first eluting isomer (45 mg) was designated (*S) which underwent further preparative HPLC purification (Xtimate C18, 150×40 mm×10 μm column, eluent: 20% to 50% (v/v) CH₃CN in H₂O with 0.2% HCOOH) to afford the title compound (30.1 mg) as a white powder after lyophilization: MS (ESI): mass calcd. for C₃₉H₄₉F₂N₇O₇S, 797.3 m/z found, 798.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J=7.3 Hz, 1H), 8.30 (s, 1H), 7.78 (s, 1H), 7.77-7.50 (m, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.13 (s, 1H), 4.93 (s, 1H), 4.40-4.32 (m, 4H), 3.81-3.69 (m, 2H), 3.61-3.55 (m, 2H), 2.70 (s, 3H), 2.69-2.61 (m, 4H), 2.43-2.39 (m, 4H), 2.13 (s, 3H), 2.09 (s, 3H), 1.58-1.43 (m, 8H), 1.36-1.31 (m, 2H), 1.28 (s, 3H), 1.24 (s, 3H).

Example 643: (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The second eluting isomer (34.2 mg) for the chiral separation described in Example 644 was designated (*R): MS (ESI): mass calcd. for C₃₄H₄₇F₂N₇O₇S, 783.3 m/z found, 784.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=7.3 Hz, 1H), 7.89 (s, 1H), 7.70 (t, J=52 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 4.97 (s, 1H), 4.54 (s, 2H), 4.44 (t, J=5.8 Hz, 2H), 3.86 (t, J=11.1 Hz, 2H), 3.75-3.56 (m, 4H), 2.83 (t, J=6.0 Hz, 2H), 2.75 (s, 3H), 2.59-2.54 (m, 4H), 2.24 (s, 3H), 2.17 (s, 3H), 1.75-1.63 (m, 6H), 1.62-1.55 (m, 2H), 1.31 (s, 3H), 1.28 (s, 3H).

Example 644: (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid

The title compound (24.2 mg) was prepared using analogous reaction conditions as described in Example 640 where tert-butyl 3-(6-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (Intermediate 194) was used instead of tert-butyl 3-(4-(chloromethyl)-5-methylpyridin-2-yl)-3-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate in Step A and following separation by SFC using a chiral stationary phase (Regis (S,) Whelk-O1 column, 250 mm×50 mm, 10 μm, eluent: 50% ethanol containing 0.1% v/v 25% aqueous ammonia:CO₂) and then further purification by preparative HPLC (Xtimate C18 column, 150 mm×25 mm×5 μm (eluent: 20% to 50% (v/v) CH₃CN in water with 0.225% HCOOH) in Step B. The first eluting isomer was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₇F₂N₇O₇S, 783.3 m/z found, 784.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=7.3 Hz, 1H), 7.89 (s, 1H), 7.70 (t, J=52 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.40 (t, J=52 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 4.97 (s, 1H), 4.54 (s, 2H), 4.44 (t, J=5.8 Hz, 2H), 3.86 (t, J=11.1 Hz, 2H), 3.75-3.56 (m, 4H), 2.83 (t, J=6.0 Hz, 2H), 2.75 (s, 3H), 2.59-2.54 (m, 4H), 2.24 (s, 3H), 2.17 (s, 3H), 1.75-1.63 (m, 6H), 1.62-1.55 (m, 2H), 1.31 (s, 3H), 1.28 (s, 3H).

Example 645: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (41 mg) from the chiral separation described in Example 646 was designated (*R): MS (ESI): mass calcd. for C₃₃H₃₈N₆O₅S, 630.3; m/z found, 631.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.40-8.26 (m, 1H), 8.12-8.01 (m, 1H), 7.67-7.56 (m, 1H), 7.48-7.39 (m, 1H), 7.23-7.00 (m, 3H), 4.72 (s, 1H), 4.65-4.53 (m, 1H), 4.28-4.19 (m, 1H), 4.19-3.64 (m, 7H), 2.81 (s, 3H), 2.43 (s, 3H), 2.22 (s, 3H), 1.42-1.17 (m, 11H).

Example 646: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 651) was separated by chiral SFC (AD-H, mobile phase: 50% CO₂, 50% isopropanol with 0.1% DEA) to afford two enantiomers. The first eluting isomer (48 mg) was designated (*S): MS (ESI): mass calcd. for C₃₃H₃₈N₆O₅S, 630.3; m/z found, 631.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.26-8.21 (m, 1H), 7.98-7.94 (m, 1H), 7.72-7.65 (m, 1H), 7.37-7.32 (m, 1H), 7.28-7.23 (m, 1H), 7.11-7.01 (m, 2H), 7.01-6.96 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 4.81 (s, 1H), 4.52 (d, J=13.3 Hz, 1H), 4.31-4.18 (m, 1H), 4.11-3.79 (m, 4H), 3.70-3.59 (m, 2H), 2.81 (s, 3H), 2.35 (s, 3H), 2.16 (s, 3H), 1.37-1.07 (m, 11H).

Example 647: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The second eluting isomer (63 mg) from the chiral separation described in Example 648 was designated (*R): MS (ESI): mass calcd. for C₃₄H₄₀N₆O₅S, 644.3.2; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55-8.51 (m, 1H), 8.24-8.19 (m, 1H), 7.89-7.83 (m, 1H), 7.58-7.52 (m, 1H), 7.49-7.43 (m, 1H), 7.34-7.17 (m, 2H), 7.05-6.97 (m, 1H), 5.17-4.96 (m, 1H), 4.68-4.55 (m, 1H), 4.35-4.23 (m, 1H), 3.97-3.88 (m, 1H), 3.23-2.79 (m, 8H), 2.74 (s, 3H), 2.09 (s, 3H), 1.64-1.46 (m, 1H), 1.30-1.15 (m, 9H), 1.01-0.94 (m, 3H).

Example 648: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid isomers (Example 652) was separated by chiral SFC (AD-H, mobile phase: 50% CO₂, 50% isopropanol with 0.1% DEA) to afford two enantiomers. The first eluting isomer (63 mg) was designated (*S): MS (ESI): mass calcd. for C₃₄H₄₀N₆O₅S, 644.3.2; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56-8.50 (m, 1H), 8.25-8.19 (m, 1H), 7.90-7.83 (m, 1H), 7.59-7.51 (m, 1H), 7.49-7.42 (m, 1H), 7.36-7.15 (m, 2H), 7.04-6.97 (m, 1H), 5.19-4.97 (m, 1H), 4.65-4.56 (m, 1H), 4.34-4.25 (m, 1H), 3.97-3.89 (m, 1H), 3.27-2.80 (m, 8H), 2.74 (s, 3H), 2.08 (s, 3H), 1.68-1.44 (m, 1H), 1.30-1.13 (m, 9H), 1.04-0.93 (m, 3H).

Example 649: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (58 mg) from the chiral separation described in Example 650 was designated (*R): MS (ESI): mass calcd. for C₃₅H₄₂N₆O₅S, 658.3; m/z found, 659.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37-8.31 (m, 1H), 8.06-8.02 (m, 1H), 7.91-7.85 (m, 1H), 7.61-7.51 (m, 1H), 7.36-7.12 (m, 2H), 7.05-6.98 (m, 1H), 5.25-4.89 (m, 1H), 4.66-4.53 (m, 1H), 4.35-4.21 (m, 1H), 4.00-3.88 (m, 1H), 3.27-2.81 (m, 8H), 2.73 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.69-1.47 (m, 1H), 1.29-1.12 (m, 9H), 1.05-0.92 (m, 3H).

Example 650: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 653) was separated by chiral SFC (OD-H, mobile phase: 70% CO₂, 30% MeOH) to afford two enantiomers. The first eluting isomer (62 mg) was designated (*S): MS (ESI): mass calcd. for C₃₅H₄₂N₆O₅S, 658.3; m/z found, 659.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.37-8.32 (m, 1H), 8.06-8.02 (m, 1H), 7.90-7.85 (m, 1H), 7.59-7.52 (m, 1H), 7.37-7.14 (m, 2H), 7.03-6.99 (m, 1H), 5.24-4.91 (m, 1H), 4.66-4.52 (m, 1H), 4.36-4.23 (m, 1H), 3.99-3.88 (m, 1H), 3.13-2.82 (m, 8H), 2.73 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.55 (s, 1H), 1.29-1.15 (m, 9H), 1.03-0.93 (m, 3H).

Example 651: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The title compound (127 mg, 37% yield) was prepared using analogous conditions as described in Example 653 where tert-butyl 8′-methyl-2′,3′-dihydrospiro[azetidine-3,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 153) was used instead of tert-butyl 8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₃H₃₈N₆O₅S, 630.3; m/z found, 631.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.25-8.22 (m, 1H), 7.97-7.94 (m, 1H), 7.70-7.64 (m, 1H), 7.37-7.32 (m, 1H), 7.25 (s, 1H), 7.11-7.05 (m, 1H), 7.01-6.96 (m, 1H), 4.81 (s, 1H), 4.56-4.47 (m, 1H), 2.19-2.13 (m, 3H), 4.27-4.18 (m, 1H), 4.05-3.98 (m, 1H), 3.94-3.77 (m, 3H), 3.71-3.59 (m, 2H), 3.05-2.91 (m, 1H), 2.81 (s, 3H), 2.35 (s, 3H), 2.16 (s, 3H), 1.37-1.08 (m, 11H).

Example 652: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid

The title compound (150 mg, 39% yield) was prepared using analogous conditions as described in Example 653 where tert-butyl 2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 150) was used instead of tert-butyl 8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. MS (ESI): mass calcd. for C₃₄H₄₀N₆O₅S, 644.3.2; m/z found, 645.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 8.69-8.37 (m, 2H), 8.31-8.22 (m, 1H), 7.47-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.24-7.18 (m, 1H), 7.13-7.06 (m, 1H), 7.05-6.97 (m, 1H), 5.00 (s, 1H), 4.87-4.75 (m, 1H), 4.27-4.16 (m, 1H), 3.84-3.40 (m, 5H), 3.28 (d, J=12.2 Hz, 2H), 2.94 (s, 3H), 2.20 (s, 3H), 2.00-1.63 (m, 3H), 1.56-1.16 (m, 11H).

Example 653: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Tert-butyl 2′-(5-(1-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-methoxy-2,2-dimethyl-3-oxopropyl)-2-methylbenzyl)-8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide. Methyl 3-(3-(chloromethyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoate (Intermediate 184, 300 mg, 0.7 mmol) was dissolved in ACN (3.5 mL). Tert-butyl 8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (Intermediate 152, 281.7 mg, 0.735 mmol) and potassium carbonate (393 mg, 2.84 mmol) were added and the reaction was stirred at 80° C. for 2 hours. After this time, the reaction was allowed to cool to room temperature, then was diluted with water and EtOAc and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound that was carried forward without further purification (524.1 mg, 92% yield). MS (ESI): mass calcd. for C₄₁H₅₂N₆O₇S, 772.4; m/z found, 773.3 [M+H]⁺.

Step B: 3-(3-((1-(Tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid. LiOH solution (2M, 0.35 mL, 0.7 mmol), 1,4-dioxane (2 mL) and water (1.5 mL) were added to tert-butyl 2′-(5-(1-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-methoxy-2,2-dimethyl-3-oxopropyl)-2-methylbenzyl)-8′-methyl-2′,3′-dihydrospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]-1-carboxylate 1′,1′-dioxide (516 mg, 0.668 mmol), and the resulting mixture was stirred at 75° C. for 8 hours. Additional 2M LiOH solution (1 mL) and 1,4-dioxane (2 mL) were added and the reaction was stirred at 80° C. overnight. Additional 2M LiOH solution (1 mL) and 1,4-dioxane (1 mL) were added and the reaction was stirred at 80° C. for an additional night. After this time, the reaction was allowed to cool to room temperature, and was acidified to pH 4 using 1M HCl. The biphasic mixture was separated and the aqueous layer was extracted with DCM. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound that was carried forward without further purification (440 mg, 87% yield). MS (ESI): mass calcd. for C₄₀H₅₀N₆O₇S, 758.3; m/z found, 759.3 [M+H]⁺.

Step C: (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. A solution of 20% TFA in DCM (6 mL) was added to 3-(3-((1-(tert-butoxycarbonyl)-8′-methyl-1′,1′-dioxidospiro[piperidine-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-3-(1-cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid (440 mg, 0.58 mmol) and the resulting solution was stirred at room temperature for 1.25 hours. The reaction was concentrated under reduced pressure, then concentrated under reduced pressure from EtOAc three times. The material was purified by preparative acidic HPLC (XBridge C₁₈, acetonitrile-water containing 0.05% TFA) to provide the title compound (164 mg, 43% yield). MS (ESI): mass calcd. for C₃₅H₄₂N₆O₅S, 658.3; m/z found, 659.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 8.10-7.98 (m, 1H), 7.48-7.30 (m, 2H), 7.24-7.16 (m, 1H), 7.14-6.96 (m, 2H), 5.00 (s, 1H), 4.86-4.75 (m, 1H), 4.28-4.16 (m, 1H), 3.80-3.41 (m, 5H), 3.39-3.16 (m, 2H), 2.94 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H), 1.97-1.63 (m, 3H), 1.48-1.14 (m, 11H).

Example 654: (*R)-3-(5-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer (38 mg) in the chiral separation described in Example 655 was designated (*R/*R): MS: mass calcd. for C₃₂H₃₃F₃N₈O₄S, 682.2; m/z found, 683.3. ¹H NMR (500 MHz, CDCl₃) δ 8.51-8.44 (m, 2H), 8.23-8.19 (m, 1H), 8.12-8.07 (m, 1H), 7.66 (s, 1H), 7.35-7.31 (m, 1H), 4.93 (s, 1H), 4.66-4.52 (m, 2H), 4.41-4.34 (m, 1H), 4.14-4.05 (m, 1H), 3.39-3.24 (m, 2H), 3.17-3.08 (m, 1H), 2.84 (s, 3H), 2.48 (s, 3H), 1.85-1.60 (m, 4H), 1.51-1.45 (m, 1H), 1.45-1.32 (m, 6H), 1.28-1.24 (m, 1H).

Example 655: (*R)-3-(5-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second peak in chiral separation described in Example 657 was further purified by chiral SFC (AS-H, mobile phase: 80% CO₂, 20% MeOH) to afford two isomers. The first eluting isomer (42 mg) was designated (*R/*S): MS: mass calcd. for C₃₂H₃₃F₃N₈O₄S, 682.2; m/z found, 683.2. ¹H NMR (500 MHz, CDCl₃) δ 8.52 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.20 (s, 1H), 8.10 (d, J=7.0 Hz, 1H), 7.64 (s, 1H), 7.33 (d, J=7.4 Hz, 1H), 4.96 (s, 1H), 4.66-4.52 (m, 2H), 4.41-4.33 (m, 1H), 4.12-4.05 (m, 1H), 3.38-3.22 (m, 2H), 3.15-3.06 (m, 1H), 2.85 (s, 3H), 2.48 (s, 3H), 1.84-1.64 (m, 4H), 1.51-1.46 (m, 1H), 1.46-1.34 (m, 6H), 1.26 (s, 1H).

Example 656: (*S)-3-(5-(((*R)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

The second eluting isomer from the first peak (37 mg) in the chiral separation described in Example 657 was designated (*S/*R): MS: mass calcd. for C₃₂H₃₃F₃N₈O₄S, 682.2; m/z found, 683.3. ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, J=2.1 Hz, 1H), 8.41 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.32 (d, J=7.3 Hz, 1H), 4.85 (s, 1H), 4.72-4.64 (m, 1H), 4.56-4.47 (m, 1H), 4.42-4.35 (m, 1H), 4.18-4.09 (m, 1H), 3.54-3.44 (m, 1H), 3.39-3.30 (m, 1H), 3.23-3.14 (m, 1H), 2.88-2.78 (m, 4H), 2.45 (s, 3H), 1.85-1.65 (m, 4H), 1.40-1.31 (m, 6H), 1.28-1.23 (m, 1H).

Example 657: (*S)-3-(5-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: Methyl 3-(5-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. A solution of methyl 3-((5-(hydroxymethyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 185, 511 mg, 1.17 mmol), 3-chloro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (Intermediate 95, 507 mg, 1.76 mmol), and triphenylphosphine (494 mg, 1.88 mmol) in THF (6 mL) was stirred at room temperature for 1 minute. DBAD (438 mg, 1.90 mmol) was added and the solution was stirred at room temperature for 30 minutes, followed by 50° C. for 30 minutes. Additional 3-chloro-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepine 5,5-dioxide (250 mg), triphenylphosphine (300 mg), DBAD (300 mg) and THF (6 mL) were added, and the reaction was stirred at 50° C. overnight. The reaction was concentrated and purified by flash column chromatography (0-100% EtOAc/hexanes) to provide the title compound which was used without further purification (400 mg, 48% yield). MS (ESI): mass calcd. for C₃₂H₃₅ClF₃N₇O₄S, 705.2; m/z found, 706.2 [M+H]⁺.

Step B: 3-(5-((3-Chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. 2M Aqueous lithium hydroxide (1.5 mL, 3.0 mmol) was added to a solution of methyl 3-(5-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (400 mg, 0.57 mmol) in 1,4-dioxane (5 mL). The reaction was stirred at 75° C. overnight then allowed to cool to room temperature. 1 M aqueous HCl solution was added until the pH was 4. EtOAc was added and the resulting biphasic mixture was separated. The aqueous layer was extracted with EtOAc. These extractions resulted in several organic solvent fractions which were combined, dried over MgSO₄, filtered, and concentrated to dryness under reduced pressure to provide the title compound which was used without further purification (417 mg, 106% yield). MS (ESI): mass calcd. for C₃₁H₃₃ClF₃N₇O₄S, 691.2; m/z found, 692.2 [M+H]⁺.

Step C: 3-(5-((3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. DMA (3 mL) was added to a mixture of 3-(5-((3-chloro-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (417 mg, 0.602 mmol), zinc cyanide (144.5 mg, 1.23 mmol), XPhos Pd G2 (53.3 mg, 0.068 mmol), and zinc powder (20 mg, 0.3 mmol). Argon was bubbled through the reaction mixture for 1 minute, then the reaction was heated to 120° C. for 2 hours. After this time, the reaction was allowed to cool to room temperature, then was filtered and purified by preparative basic HPLC (XBridge C₁₈, acetonitrile-water, 20 mM NH₄OH) to provide the title compound (285 mg, 69% yield). MS (ESI): mass calcd. for C₃₂H₃₃F₃N₈O₄S, 682.2; m/z found, 683.3 [M+H]⁺.

Step D: (*S)-3-(5-(((*S)-3-Cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid. The mixture of 3-(5-((3-cyano-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid isomers was initially separated by chiral SFC (SFC-B, mobile phase: 70% CO₂, 30% MeOH) and then chiral SFC (AS-H, mobile phase: 80% CO₂, 20% MeOH) to afford two peaks, a first eluting isomer (*S/*S) and a second eluting isomer, (*S/*R). The first eluting isomer (35 mg): MS: mass calcd. for C₃₂H₃₃F₃N₈O₄S, 682.2; m/z found, 683.3. ¹H NMR (500 MHz, CDCl₃) δ 8.50-8.43 (m, 2H), 8.22 (d, J=2.2 Hz, 1H), 8.07 (d, J=7.0 Hz, 1H), 7.75 (s, 1H), 7.32 (d, J=7.4 Hz, 1H), 4.89 (s, 1H), 4.71-4.62 (m, 1H), 4.58-4.48 (m, 1H), 4.46-4.35 (m, 1H), 4.19-4.10 (m, 1H), 3.52-3.44 (m, 1H), 3.40-3.30 (m, 1H), 3.25-3.15 (m, 1H), 2.91-2.79 (m, 4H), 2.47 (s, 3H), 1.87-1.66 (m, 4H), 1.45-1.30 (m, 6H), 1.28-1.24 (m, 1H).

Example 658: (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid

Step A: tert-Butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. The title compound (200 mg, 34%) was prepared using analogous conditions as described in Example 126 where 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide (Intermediate 137) was used instead of 8′-methyl-7′-((2-(piperidin-1-yl)ethoxy)-2,2′,3,3′,5,6-hexahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepine]1′,1′-dioxide and tert-butyl (*R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate (Intermediate 135) instead of benzyl (*S)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoate in step A. mass calcd. for C₄₁H₅₁F₃N₆O₆S, 812.4; m/z found, 407.3 [M+2H]²⁺.

Step B: (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. To a 25-mL round bottom flask fitted with a reflux condenser was added tert-Butyl (*R)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (200 mg 0.246 mmol), DCM (4.0 mL) and TFA (1 mL). The mixture was heated to 50° C. for 1.5 h then cooled, and solvent removed under reduced pressure. The mixture was treated with ethyl acetate/hexanes and the precipitated material was dried under vacuum to provide the title compound (180 mg, 84%) as the TFA salt. MS (ESI): mass calcd. for C₃₇H₄₃F₃N₆O₆S, 756.3; m/z found, 757.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 9.70 (s, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.01 (d, J=1.0 Hz, 1H), 7.25-7.19 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 4.79 (s, 1H), 4.59-4.56 (m, 2H), 4.27-4.08 (m, 2H), 3.63-3.37 (m, 6H), 3.18-3.13 (m, 2H), 2.64 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 2.08-2.01 (m, 2H), 1.91-1.88 (m, 2H), 1.31 (s, 3H), 1.24 (s, 3H), 0.98-0.90 (m, 2H), 0.64-0.45 (m, 2H).

Example 659: (*S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-74(S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

The mixture of (R/S)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-74(S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid isomers (Example 618) was separated by chiral SFC (IC, mobile phase: 55% CO₂, 45% EtOH with 0.3% iPrNH₂) to afford two diastereomers. The first eluting isomer (131 mg) was designated (*S): MS (ESI): mass calcd. for C₄₁H₅₃N₇O₅S, 755.4; m/z found, 756.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66-7.62 (m, 1H), 7.57-7.52 (m, 2H), 7.17-7.11 (m, 1H), 7.08-7.03 (m, 1H), 7.01-6.97 (m, 1H), 6.39 (d, J=7.5 Hz, 1H), 4.79 (s, 1H), 4.23-3.91 (m, 4H), 2.62 (s, 3H), 2.47-2.30 (m, 6H), 2.29-2.21 (m, 4H), 2.11-2.04 (m, 3H), 1.52-1.42 (m, 4H), 1.42-1.34 (m, 2H), 1.28-1.11 (m, 11H), 1.08-1.01 (m, 3H), 0.97-0.81 (m, 2H), 0.48-0.40 (m, 1H), 0.35-0.27 (m, 1H).

Example 660: (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((S)-1-(piperidin-1-yl)propan-2-yl)amino)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic acid

The second eluting isomer (153 mg) from the chiral separation described in Example 659 was designated (*R): MS (ESI): mass calcd. for C₄₁H₅₃N₇O₅S, 755.4; m/z found, 756.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.63-7.59 (m, 1H), 7.57-7.51 (m, 2H), 7.18-7.14 (m, 1H), 7.09-7.04 (m, 1H), 7.00-6.96 (m, 1H), 6.41-6.37 (m, 1H), 4.80 (s, 1H), 4.22-3.91 (m, 4H), 2.64 (s, 3H), 2.45-2.28 (m, 6H), 2.27-2.21 (m, 4H), 2.10-1.99 (m, 3H), 1.50-1.34 (m, 6H), 1.24-1.10 (m, 14H), 0.90-0.85 (m, 2H), 0.43-0.27 (m, 2H).

Example 661: (*S)-3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

Step A: (*S)-Benzyl 3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate. 7′-((2-(4-Fluoropiperidin-1-yl)ethoxy)-8′-methyl-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (430 mg, 1.12 mmol, Intermediate 202) was added to a solution of (*S)-benzyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 203, 620 mg, 1.17 mmol), K₂CO₃ (618 mg, 4.47 mmol), and CH₃CN (20 mL). The resulting mixture was stirred at 90° C. for 16 hours before concentrating to dryness under reduced pressure. The residue was diluted with water (10 mL) and the mixture extracted with ethyl acetate (3×). These extractions resulted in several fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluent: petroleum ether/ethyl acetate; 10:1 to 0:1, gradient) to afford the title compound (700 mg, 68%). MS (ESI): mass calcd. for C₄₅H₅₀F₄N₆O₆S 878.3 m/z found 879.5 [M+H]⁺.

Step B: (*S)-3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid. LiOH.H₂O (335 mg, 7.98 mmol) was added to a solution of (*S)-benzyl 3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (700 mg, 0.796 mmol), 1,4-dioxane (10 mL), and H₂O (10 mL). The resulting mixture was stirred while heating at 75° C. for 12 hours before cooling to room-temperature and concentrating to dryness under reduced pressure. The residue was diluted with H₂O (5 mL), pH adjusted to 6-7 with aq. HCl (1 M), and extracted with ethyl acetate (2×). These extractions resulted in several fractions that were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by reverse-phase preparative HPLC (eluent: CH₃CN/H₂O with 0.225% HCOOH; 28% to 58% (v/v), gradient) to afford the title compound (321 mg, 50%) as a white solid. MS (ESI): mass calcd. for C₃₄H₄₄F₄N₆O₆S 788.3 m/z found 789.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.1 Hz, 1H), 7.94 (s, 1H), 7.31-7.18 (m, 2H), 7.15-7.05 (m, 2H), 4.83-4.02 (m, 6H), 2.77-2.56 (m, 9H), 2.46-2.31 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H), 1.97-1.60 (m, 4H), 1.28 (s, 3H), 1.22 (s, 3H), 1.00-0.86 (m, 2H), 0.59-0.35 (m, 2H).

Example 662: (*S)-3-(3-((7′-((2-(4-fluoropiperidin-1-yl)ethoxy)-8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid

The title compound (350 mg, 62%) was prepared using analogous conditions as described in Example 661 where (*R)-benzyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate (Intermediate 204) was used instead of (*S)-benzyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoate in step A. MS (ESI): mass calcd. for C₃₈H₄₄F₄N₆O₆S 788.3 m/z found 789.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d, J=7.1 Hz, 1H), 7.94 (s, 1H), 7.28-7.04 (m, 4H), 4.85-4.56 (m, 2H), 4.45-4.30 (m, 2H), 4.24-4.00 (m, 2H), 3.22-2.92 (m, 1H), 2.72-2.58 (m, 8H), 2.45-2.31 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H), 1.88-1.67 (m, 4H), 1.28 (s, 3H), 1.21 (s, 3H), 0.99-0.84 (m, 2H), 0.60-0.39 (m, 2H).

Example 663: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid

Step A: Benzyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate. SOCl₂ (0.3 mL, 4 mmol) was added to a solution consisting of benzyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (Intermediate 199, 400 mg, 0.827 mmol) and dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 1 hour, then concentrated to dryness under reduced pressure to provide the title compound (415 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₃₀H₃₂ClN₃O₂ 502.05; m/z found, 502.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.42 (s, 1H), 7.11-7.04 (m, 6H), 7.00 (s, 1H), 6.94 (d, J=7.8 Hz, 1H), 5.23 (d, J=11.8 Hz, 1H), 4.79 (d, J=11.8 Hz, 1H), 4.64 (s, 1H), 4.48 (s, 2H), 2.72 (s, 3H), 2.35 (s, 3H), 2.13 (br s, 1H), 1.44 (s, 3H), 1.41-1.38 (m, 1H), 1.36 (s, 3H), 1.34-1.18 (m, 3H).

Step B: Benzyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate. Benzyl (*S)-3-(3-(chloromethyl)-4-methylphenyl)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethylpropanoate (415 mg, 0.827 mmol), 8′-methyl-7′-((2-(pyrrolidin-1-yl)ethoxy)-2′,3′-dihydrospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepine] 1′,1′-dioxide (Intermediate 137, 321 mg, 0.908 mmol), K₂CO₃ (343 mg, 2.48 mmol) and acetonitrile (20 mL) were combined and the resulting mixture was stirred for 16 hours at 80° C. After this time, the suspension was filtered and the filter cake was washed with acetonitrile (5×3 mL). The filtrate was concentrated to dryness under reduced pressure to provide the title compound (677 mg), which was used in the next step without further purification. MS (ESI): mass calcd. for C₄₆H₅₄N₆O₆S 819.02; m/z found, 819.5 [M+H]⁺.

Step C: (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid. Benzyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoate (677 mg, 0.827 mmol), MeOH (20 mL), and wet Pd/C (100 mg, 10 wt. %) were added combined and the resulting mixture was stirred under H₂ (15 psi) at room temperature for 3 hours. After this time, the suspension was filtered, and the filter cake was washed with MeOH (5 mL×3). The filtrate was concentrated to dryness under reduced pressure, combined with another batch of the same compound, and purified by preparative acidic HPLC (Xtimate C18, 150 mm×25 mm×5 μm column, eluent: 25-55% CH₃CN and H₂O with 0.225% HCOOH) to provide the title compound (343.6 mg) as a white solid. MS (ESI): mass calcd. for C₃₉H₄₈N₆O₆S 728.90; m/z found, 729.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J=7.3 Hz, 1H), 7.92 (s, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.7 Hz, 2H), 6.91 (d, J=7.3 Hz, 1H), 4.65 (s, 1H), 4.36 (t, J=5.6 Hz, 2H), 4.19-4.14 (m, 1H), 4.11-4.06 (m, 1H), 3.55-3.53 (m, 4H), 2.85 (t, J=5.5 Hz, 2H), 2.60 (s, 3H), 2.32-2.28 (m, 1H), 2.20 (s, 3H), 2.14 (s, 3H), 1.75-1.61 (m, 4H), 1.23 (s, 3H), 1.17 (s, 3H), 1.08-1.01 (m, 2H), 1.01-0.86 (m, 4H), 0.63-0.37 (m, 4H).

Example 664: (*R)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′II)-yl)methyl)phenyl)propanoic acid

The title compound (326.1 mg) was prepared using analogous conditions as described in Example 663 where benzyl (*R)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. (Intermediate 200) was used instead of benzyl (*S)-3-(3-cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate and the final compound was purified by preparative acidic HPLC (Boston Green ODS, 150 mm×30 mm×5 μm column, eluent: 25-55% CH₃CN and H₂O with 0.225% HCOOH). MS (ESI): mass calcd. for C₃₉H₄₈N₆O₆S 728.90; m/z found, 729.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (d, J=7.3 Hz, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.11 (d, J=7.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 4.68 (s, 1H), 4.39 (t, J=5.5 Hz, 2H), 4.22-4.18 (m, 1H), 4.12 (d, J=14.8 Hz, 1H), 3.57-3.55 (m, 4H), 2.87 (t, J=5.6 Hz, 2H), 2.62 (s, 3H), 2.33-2.29 (m, 1H), 2.28-2.20 (m, 3H), 2.17 (s, 3H), 1.70 (s, 4H), 1.27 (s, 3H), 1.21 (s, 3H), 1.08 (d, J=2.6 Hz, 2H), 1.03-0.91 (m, 4H), 0.67-0.44 (m, 4H).

Example 665: (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-48′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′ H)-yl)methyl)pyridin-2-yl)propanoic acid

The title compound was prepared as described in Scheme 1. MS (ESI): mass calcd. for C₃₁H₃₆N₆O₅S, 604.2; m/z found, 605.2 [M+1-1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 8.32 (s, 1H), 8.31-8.29 (m, 1H), 8.01-7.99 (m, 1H), 7.59-7.53 (m, 2H), 7.03 (s, 1H), 5.00 (s, 1H), 4.66 (q, J=7.1 Hz, 2H), 4.23-4.10 (m, 2H), 3.76-3.58 (m, 1H), 3.52-3.40 (m, 1H), 2.82 (s, 3H), 2.33 (s, 3H), 2.17 (s, 3H), 1.47 (t, J=7.3 Hz, 3H), 1.29 (s, 3H), 1.20 (s, 3H), 0.95-0.81 (m, 2H), 0.67-0.51 (m, 2H).

Biological Assay.

Binding potency was assessed using a ThermoFluor® assay and cell based activity in HEK cells was assesses using an ARE assay.

The ARE assay utilizes a luciferase reporter cell line where the signal is proportional to NrF2 activation of the ARE. The cell line is commercially available from Promega and was prepared by stably transfecting HEK293 cells with a vector (pGL4.11) which contains the ARE response element upstream of a minimal promoter. The promoter drives expression of luc2 firefly luciferase gene. Upon disruption of KEAP1-Nrf2 binding by compound, Nrf2 translocates into the nucleus where it binds to the ARE and activates transcription of luciferase.

The materials used in this ARE assay are as follows: Glo-Response ARE-luc2P HEK293 cell line and One-Glo Luciferase Assay System were purchased from Promega (Madison, Wis.). Dulbecco's Modified Eagle medium ((DMEM), low glucose, GlutaMAX, pyruvate), fetal bovine serum (certified, heat inactivated), hygromycin B, Dulbecco's phosphate-buffered saline were purchased from Life Technologies (Grand Island, N.Y.). Penicillin, streptomycin solution (100×) and 0.05% trypsin-EDTA were purchased from Corning (Manassas, Va.). DMSO was purchased from EMD Millipore.

The ARE assay protocol is as follows: cells were maintained in growth medium (DMEM +10% FBS, 200 μg/mL hygromycin B, p-s) between 20-90% confluency by splitting twice per week. One day before the assay, cells were trypsinized, counted to determine viable cell count, and re-suspended in assay medium (DMEM+10% FBS, p-s) at 250,000 cells/mL. Five thousand cells per well were plated in a 384 well, PDL coated, solid white tissue culture plate (Greiner 781201-906) with 100% DMSO. 100% DMSO was used as the low control. A 11-point dose series of the control compound was included on every plate. Compounds were spotted to an intermediate plate (Greiner #781280 V-bottom 384 well plate) using the Echo acoustic dispenser (Labscyte San Jose, Calif.). Spot size was 240 nL.

On the day of the assay, 60 mL per well of assay medium was added to the pre-spotted plate to make 2× compound stocks using the Combi (Thermo Waltham, Mass.). Compound and medium were mixed on the Janus and 20 mL of 2× compound stock was added to the cell plate which already contained 20 mL of assay medium from cell plating. The top dose of compound (final) was typically 20 or 2 mM and the final DMSO concentration was 0.2%. The plates were returned to the tissue culture incubator for 24 hours.

The next day, luciferase activity was measured according to the manufacturer's protocol for One-Glo luciferase reagent. The plates were removed from the incubator and allowed to equilibrate to room temperature for 30 min. Forty microliters of One-Glo reagent (equilibrated to room temperature) was added per well using the Combi. The plates were mixed on an orbital shaker for 3 min. Luminescence was read on the BMG Pherastar multiplate reader (Cary, N.C.) using the luminescence protocol (1 sec interval).

The dose-response data were analyzed in Genedata Screener using 4PL nonlinear regression model. Raw luminescence counts as well as normalized values were used for data analysis.

Results for the compounds tested in the ARE assay are presented in Table 4 as an average of results obtained.

The ThermoFluor® is a fluorescence based assay (Tf) that estimates ligand binding affinities by measuring the effect of a ligand on protein thermal stability (Pantoliano, M. W., et al., J. Biomol. Screen 2010, 6, 429-40.). This approach is applicable to a wide variety of systems, and rigorous in theoretical interpretation through quantitation of equilibrium binding constants (K_(D)).

In a ThermoFluor® experiment where protein stability is monitored as the temperature is steadily increased, an equilibrium binding ligand causes the midpoint of an unfolding transition (T_(m)) to occur at a higher temperature. The shift in the melting point described as a ΔT_(m) is proportional to the concentration and affinity of the ligand. The compound potency may be compared as a rank order of either ΔT_(m) values at a single compound concentration or in terms of K_(D) values, estimated from concentration response curves.

The details of the KEAP1 KELCH ThermoFluor® Assay Construct are as follows: Kelch domain of human KEAP 1 (321-624 aa) was used in the assay. The protein was expressed in E. coli with 6His tag that was cleaved prior to receipt for use.

ThermoFluor® experiments were carried out using instruments owned by Janssen Research and Discovery, L.L.C. through its acquisition of 3-Dimensional Pharmaceuticals, Inc. 1,8-ANS (Invitrogen) was used as a fluorescent dye. Protein (KEAP Kelch) and compound solutions were dispensed into black 384-well polypropylene PCR microplates (Abgene) and overlayed with silicone oil (1 μL, Fluka, type DC 200) to prevent evaporation.

Reference wells contained KEAP Kelch without compounds, and the assay conditions were as follows: 1.1 μM (0.037 mg/mL) KEAP Kelch, 80 μM 1,8-ANS, 25 mM PIPES, pH 7.0, 100 mM NaCl, 0.002% Tween-20.

The binding affinity was estimated as described previously (Matulis, D. et al., Biochemistry 2005, 44, 5258-66) using thermodynamic parameters of protein unfolding listed below.

ΔH_((Tm))=50 kcal/mol

ΔC_(p(Tm))=4 kcal/mol

Reference KEAP Kelch T_(m): 49.5+/−0.4

ThermoFluor assay data are presented in Table 4 as an average of results obtained.

TABLE 4 ThermoFluor binding and ARE cell-based assay data Example # Tf K_(d) (nM) ARE assay (nM) 1 0.042 35 2 0.162 180 3 0.041 35 4 0.24 79 5 0.518 110 6 0.089 42 7 0.127 74 8 0.188 660 9 <1 3.8 10 <1 5.2 11 0.024 4.2 12 * 2.7 13 0.079 37.8 14 * 0.7 15 * 0.3 16 838 233 17 * 3.6 18 * 1.5 19 1284 789 20 0.081 6.3 21 0.273 28 22 0.081 3.9 23 0.278 8.3 24 0.264 4.1 25 2.123 21 26 0.174 32 27 * 28.8 28 <1 23.5 29 <1 50.9 30 <1 73.7 31 * 9.9 32 * 13.6 33 <1 30.6 34 <1 118.7 35 <1 65.7 36 <1 15.2 37 <1 25.7 38 <1 7.2 39 4250 1260 40 NT NT 41 <1 46 42 7540 3460 43 NT NT 44 <1 54.3 45 42600 6555 46 <1 71.9 47 <1 17.9 48 820 6272 49 <1 71.9 50 <1 52 51 0.97 645.9 52 <1 8.2 53 <1 3.9 54 1790 955.6 55 <1 123.7 56 <1 48 57 5670 6658 58 2.4 225.7 59 1.2 115.8 60 41150 12313 61 <1 41.7 62 <1 19.2 63 14550 3279.9 64 <1 304.4 65 2.5 360 66 1 260 67 0.34 23 68 1.4 250 69 0.16 28.5 70 1.9 180 71 2.6 1160 72 5.4 1970 73 3 600 74 <1 24 75 <1 14 76 4.8 136.4 77 0.42 15.7 78 NT 8.9 79 5.6 153.4 80 8 305.9 81 5.5 176 82 80 3350 83 <1 232 84 <1 80.5 85 2.2 1508 86 2.4 6241 87 1.3 2529 88 0.01 >20,000 89 0.0054 6.9 90 * 4.2 91 <1 14.4 92 <1 28.6 93 <1 10 94 <1 54.2 95 2.5 1080 96 1.1 491 97 10 5288 98 * 16 99 <1 5.8 100 <1 13.3 101 <1 577.2 102 <1 695.8 103 1.6 9132 104 NT NT 105 16 14,427 106 21 >20,000 107 <1 259.1 108 <1 405.9 109 * 128 110 <1 485.3 111 <1 588.2 112 <1 1312 113 NT 490.3 114 * 145 115 <1 132.8 116 2680 991.1 117 <1 424.8 118 <1 324.5 119 <1 166.1 120 8560 19,372 121 <1 156.6 122 8930 12,990 123 <1 28.9 124 <1 28.8 125 <1 140.5 126 <1 6 127 <1 11.8 128 <1 307.6 129 <1 6.8 130 * 54.8 131 * 1.6 132 * NT 133 <1 2 134 <1 61.3 135 1.8 24 136 <1 8.3 137 5.8 300 138 <1 14 139 <1 3.3 140 <1 19 141 <1 3.9 142 <1 1.1 143 <1 45 144 <1 3.1 145 <1 1.1 146 <1 4.2 147 1.5 19 148 <1 15 149 8.6 250 150 <1 56 151 <1 10 152 0.12 6.5 153 <1 3 154 <1 59 155 <1 6.1 156 2.1 3.6 157 ~3.2 62 158 <1 6.2 159 ~1.2 34 160 <1 19,000 161 2.8 15,890 162 <1 2440 163 <1 2,750 164 2.3 11,170 165 <1 1,490 166 <1 7,020 167 <1 1,140 168 <1 480 169 1.2 5,910 170 <1 110 171 <1 88 172 <1 19 173 4 540 174 <1 15 175 <1 5.3 176 <1 31 177 49 1,390 178 30 440 179 58 2,040 180 190 2,880 181 110 1,110 182 180 1,390 183 1.6 370 184 1.4 130 185 12 2,720 186 * 47 187 <1 550 188 <1 17 189 <1 11 190 <1 57 191 * 1.9 192 <1 1.4 193 * 1.7 194 * 2 195 <1 5.7 196 <1 15 197 <1 1.8 198 * 5.3 199 * 3.3 200 <1 61 201 300 >20,000 202 * 13 203 * 150 204 * 5.9 205 <1 130 206 * 14 207 <1 11 208 <1 19 209 <1 8.8 210 <1 7.7 211 1.1 42 212 <1 3.7 213 <1 8 214 <1 5.1 215 <1 3.3 216 2 38 217 <1 11 218 <1 6.6 219 * 4.5 220 <1 61 221 19 580 222 14 350 223 190 5,460 224 * 20 225 * 5 226 6 160 227 <1 22 228 <1 10 229 17,000 2,430 230 <1 480 231 <1 7 232 <1 2.6 233 <1 80 234 <1 3.3 235 <1 1.9 236 <1 6.8 237 1.5 19 238 <1 9.7 239 1.9 44 240 <1 85 241 <1 28 242 1.8 110 243 <1 35 244 <1 35 245 <1 140 246 <1 87.3 247 <1 225.2 248 <1 48.6 249 <1 28.6 250 <1 32.8 251 <1 24.1 252 <1 21.0 253 <1 1168.2 254 <1 3398.6 255 <1 921.7 256 <1 378.8 257 <1 574.1 258 <1 427.7 259 <1 200.9 260 <1 101.0 261 <1 1389.6 262 1.089 14.7 263 14.73 1158.2 264 <1 18.3 265 <1 31.2 266 <1 14.6 267 <1 90.4 268 <1 516.5 269 <1 365.1 270 1.28 2417.1 271 <1 22.9 272 <1 10.9 273 <1 25.8 274 1.19 51.2 275 8.69 399.4 276 <1 112.3 277 1.29 101.8 278 <1 467.2 279 <1 235.0 280 <1 4007.7 281 <1 480.5 282 <1 293.2 283 <1 4167.7 284 1.65 212.8 285 1.1 128.9 286 3.39 504.1 287 <1 28.1 288 <1 122.6 289 <1 19.3 290 <1 8.8 291 <1 86.8 292 <1 68.3 293 2.55 898.7 294 1.61 270.1 295 8.07 2090.3 296 <1 13.6 297 <1 6.0 298 <1 21.5 299 * 11.4 300 <1 5.0 301 <1 4.7 302 <1 2.8 303 <1 27.1 304 <1 2.9 305 <1 1.7 306 <1 9.4 307 * 2.0 308 <1 1.4 309 * 0.9 310 * 3.0 311 <1 9.3 312 <1 13.1 313 * 1.1 314 <1 1.0 315 287.1 147.8 316 * 1.3 317 <1 1.9 318 1990 598.3 319 NT 44.5 320 830.6 19422.3 321 <1 22.0 322 * 22.4 323 297.5 16236.8 324 <1 16.7 325 <1 17.2 326 3235 4602.6 327 <1 6.9 328 <1 3.3 329 1878 1902.8 330 1592 7524.9 331 <1 17.1 332 <1 25.6 333 1715 3984.7 334 <1 5.2 335 2436 4622.7 336 * 1831.9 337 >10,000 >19.9986 338 <1 13.1 339 80,186 6319.8 340 1.24 629.1 341 18758 >19.9986 342 <1 5.6 343 32195 1573.6 344 * 4928.3 345 >10,000 >19.9986 346 * 49.8 347 * 3576.0 348 * 19.2 349 * 1535.3 350 * 23.4 351 * 836.0 352 * 43.7 353 * 1405.7 354 <1 20.6 355 3070.4 1138.7 356 3547.3 11.8 357 <1 452.0 358 4464.8 23.3 359 <1 1234.0 360 <1 9.3 361 <1 60.4 362 <1 20.5 363 <1 12.9 364 NT NT 365 <1 23.9 366 <1 407.2 367 <1 78.6 368 <1 255.7 369 <1 175.7 370 <1 11.3 371 <1 6.0 372 <1 2.9 373 <1 5.4 374 <1 4.8 375 <1 11.5 376 <1 57.3 377 <1 44.9 378 <1 4.0 379 <1 12.3 380 <1 14.1 381 2824.9 427.2 382 <1 1.8 383 <1 1.2 384 246 150.2 385 <1 1.8 386 1063.2 343.2 387 1234.8 270.2 388 <1 1.0 389 <1 12.1 390 <1 90.9 391 <1 26.7 392 <1 11.3 393 2103.8 4796.2 394 <1 40.1 395 <1 15.7 396 21782 4901.2 397 <1 11.0 398 <1 1.4 399 <1 92.9 400 <1 4.1 401 <1 2.7 402 <1 27.9 403 <1 20.8 404 <1 19.6 405 <1 7.4 406 * 3.6 407 * 1.47 408 1283.51 789.59 409 <1 2.64 410 2401.6 1220.67 414 * 11.04 415 * 5.10 416 * 2.53 417 <1 1.77 418 <1 0.96 419 <1 4.15 420 268.472 57.80 421 * 0.24 422 <1 1.30 423 586.273 409.07 424 <1 1.65 425 <1 96.89 426 0.90 427 293.43 428 <1 398.84 429 * 17840.20 430 7830.69 647.14 431 <1 2.84 432 <1 102.66 433 * 237.14 434 1.51496 3869.90 435 118.632 >20,000 436 <1 2228.44 437 1.83992 4375.22 438 233.722 >20,000 439 1.25603 2441.18 440 <1 713.51 441 60.3393 >20,000 442 <1 553.35 443 <1 1104.84 444 21.2961 >20,000 445 <1 715.81 446 <1 23.83 447 * 2.93 448 <1 217.52 449 <1 47.63 450 <1 25.10 451 <1 264.97 452 <1 116.04 453 <1 162.29 454 * 38.28 455 <1 797.63 456 <1 413.52 457 1.02 478.85 458 <1 276.31 459 1.19 202.96 460 2.73 119.15 461 1.19 68.66 462 13.73 2931.57 463 <1 27.65 464 * 24.68 465 <1 153.85 466 <1 123.91 467 <1 79.32 468 <1 502.34 469 <1 608.28 470 <1 472.50 471 <1 2632.69 472 <1 244.96 473 <1 103.66 474 <1 1577.61 475 <1 406.35 476 <1 218.88 477 2.60555 1682.29 478 <1 57.64 479 <1 48.84 480 <1 251.59 481 <1 1290.33 482 <1 701.13 483 <1 3450.64 484 <1 225.74 485 <1 155.56 486 1.83 332.58 487 <1 18.27 488 * 11.92 489 <1 29.79 490 <1 5.85 491 <1 5.53 492 <1 12.86 493 <1 1228.57 494 <1 577.30 495 <1 2861.54 496 <1 7.65 497 <1 4.47 498 <1 14.66 499 <1 12.78 500 * 6.55 501 * 34.54 502 * 3.92 503 * 2.58 504 * 7.22 505 NT NT 506 * 7.83 507 * 0.73 508 <1 92.66 509 <1 70.37 510 <1 313.76 511 * 1.52 512 * 3.21 513 * 1.63 514 * 1.70 515 * 1.33 516 <1 11.08 517 * 10.33 518 <1 3.48 519 <1 15.97 520 <1 15.59 521 <1 1.97 522 * 5.06 523 <1 23.88 524 * 19.66 525 <1 38.83 526 <1 60.13 527 <1 22.23 528 <1 235.51 529 <1 29.07 530 * 10.25 531 <1 113.03 532 <1 41.70 533 <1 31.34 534 <1 99.20 535 <1 146.39 536 <1 59.66 537 <1 464.30 538 <1 58.91 539 <1 76.02 540 <1 26.71 541 <1 223.41 542 <1 59.65 543 <1 42.93 544 <1 278.23 545 * 49.82 546 NT >20,000 547 602.28 9642.73 548 260.44 2741.58 549 84566.80 >20,000 551 452.90 >20,000 552 150.00 >20,000 553 769.31 >20,000 554 <1 181.18 555 <1 1.42 556 4944.24 1751.86 557 <1 0.56 558 343.48 194.98 559 * 4.69 560 <1 1.90 561 52.53 258.29 562 14.80 2487.14 563 20.96 >20,000 564 322.70 >20,000 565 59.42 >20,000 566 * 6.81 567 * 2.60 568 * 191.87 569 * 1371.51 570 <1 1117.12 571 5849.25 >20,000 572 * 391.74 573 <1 321.29 574 6746.84 14628.50 575 <1 6.62 576 <1 2.34 577 717.79 768.07 578 NT 0.00 579 <1 27.77 580 1640.97 3238.92 581 NT 0.00 582 <1 1.43 583 1614.73 765.77 584 <1 477.97 585 <1 252.81 586 6381.17 >20,000 587 <1 17.41 588 <1 7.64 589 1447.77 1965.17 590 <1 33.17 591 <1 26.12 592 <1 17.60 593 <1 89.74 594 <1 3.30 595 4.28 139.16 596 <1 3.08 597 <1 2.79 598 <1 8.85 599 <1 246.38 600 <1 4.58 601 <1 4.79 602 <1 2.72 603 <1 54.97 604 <1 8.82 605 <1 109.42 606 1733.01 >20,000 607 1363.33 7617.28 608 <1 9.12 609 634.02 >20,000 610 <1 4.42 611 12844 574.12 612 61546 19856.40 613 <1 33.24 614 <1 0.71 615 <1 1.09 616 <1 2.14 617 <1 1.15 618 NT 0.00 619 <1 4.48 620 <1 7.87 621 <1 5636.38 622 2529.3 3227.01 623 <1 7.50 624 18378.1 3662.69 625 <1 70.62 626 2979.89 229.14 627 <1 1.35 628 15428 >20,000 629 131432 >20,000 630 3.81 81.85 631 1.08 76.75 632 21227.6 18071.70 633 2261 1751.86 634 <1 9.53 635 1190.42 3594.18 636 <1 40.23 637 * 615.46 638 <1 20.10 639 1823.48 5170.11 640 <1 73.88 641 * 2294.03 642 <1 36.60 643 2418.8 9783.63 644 <1 51.69 645 <1 1.50 646 * 66.68 647 <1 11.61 648 * 1352.07 649 1450.11 4746.79 650 <1 4.36 651 NT NT 652 NT NT 653 NT NT 654 * 6884.94 655 <1 138.01 656 * 3592.53 657 <1 74.99 658 1213.67 6053.41 659 <1 NT 660 681.40 234.53 661 <1 NT 662 568.20 308.04 663 <1 57.5 664 1840 >20,000 665 180 497.00 * atypical dose response curves, binding affinity is not reported, NT means that the compound was not tested in the assay. 

1-109. (canceled)
 110. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient and at least one compound selected from the group consisting of (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid; (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid; (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-54(8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid; (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*R)-3-(3-((7′-(((1R,3R)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′4(1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid; (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid; (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S) 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; and pharmaceutically acceptable salts, and combinations thereof.
 111. A compound selected from the group consisting of (*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid; (*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6 (7H)-yl)methyl)-4-methylphenyl)propanoic acid; (R/S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid; (*S)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3 f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid; (*R)-3-(3-(((*S)-5,5-Dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3 f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid; (*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid; (*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*R)-3-(3-((7′-(((1R,3R)-3-Hydroxycyclobutyl)amino)-8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-((((1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (R/S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid; (*S)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid; (*R)-3-(3-(((*S)-5,5-Dioxido-7a,8,10,11-tetrahydro-[1,4]oxazino[3,4-d]pyrido[2,3-f][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid; (*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid (*R)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid; (*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid; (*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid; (*R)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid; (R/S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*R)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid; (*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; (*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-((2-morpholinoethoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S) 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid; (*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-((2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; (*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-((2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; and pharmaceutically acceptable salts, and combinations thereof.
 112. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient and at least one compound as claimed in claim
 111. 